Amide compounds

ABSTRACT

A compound of the formula (I)  
                 
 
     wherein  
     R 1  is hydrogen, lower alkyl, lower alkenyl, halo(lower)alkyl, cyclo(lower)alkyl, lower alkoxy, lower alkylthio, acyl, optionally substituted aryl or NR 3 R 4 ;  
     R 2  is hydrogen; or aryl or heteroaryl, each of which may be substituted;  
     X is direct bond or bivalent residue derived from piperazine;  
     Y is -(A 1 ) n -(A 2 ) m -, wherein n and m are independently 0 or 1);  
                 
 
     is bivalent residue derived from arene or heteroarene; and  
                 
 
     is bivalent residue derived from arene or heteroarene, or a salt thereof. The compound of the present invention and a salt thereof inhibit apolipoprotein B (Apo B) secretion and are useful as a medicament for prophylactic and treatment of diseases or conditions resulting from elevated circulating levels of Apo B.

TECHNICAL FIELD

[0001] This invention relates to new amide compounds and salts thereofwhich inhibit apolipoprotein B (Apo B) secretion and are useful as amedicament.

BACKGROUND ART

[0002] Apo B is the main component of lipoprotein such as VLDL (very lowdensity lipoprotein), IDL (intermediate density lipoprotein) and LDL(low density lipoprotein). Compounds that inhibit Apo B secretion areuseful for the treatment of diseases or conditions resulting fromelevated circulating levels of Apo B, such as hyperlipemia,hyperlipidemia, hyperlipoproteinemia, hypercholesterolemia,hypertriglyceridemia, atherosclerosis, pancreatitis, non-insulindependent diabetes mellitus (NIDDM), obesity and coronary heartdiseases. Compounds that inhibit Apo B secretion have been described inWO96/40640, WO98/23593, WO98/56790 and WO00/32582. Compounds thatinhibit Apo B secretion are also useful in reducing intestinal fatabsorption, reducing food intake and treating obesity in combinationwith a known anti-obesity agent (EP 1 099 438, EP 1 099 439 and EP 1 099441).

DISCLOSURE OF INVENTION

[0003] This invention relates to new amide compounds.

[0004] One object of this invention is to provide new and useful amidecompounds and salts thereof that inhibit Apo B secretion.

[0005] A further object of this invention is to provide a pharmaceuticalcomposition comprising said amide compound or a pharmaceuticallyacceptable salt thereof.

[0006] Still further object of this invention is to provide a use ofsaid amide compounds or pharmaceutically acceptable salts thereof as amedicament for prophylactic and therapeutic treatment of diseases orconditions resulting from elevated circulating levels of Apo B, such ashyperlipemia, hyperlipidemia, hyperlipoproteinemia,hypercholesterolemia, hypertriglyceridemia, atherosclerosis,pancreatitis, non-insulin dependent diabetes mellitus (NIDDM), obesity,coronary heart diseases, myocardial infarction, stroke, restenosis andSyndrome X.

[0007] Another object of this invention is to provide a method forinhibiting or decreasing Apo B secretion in a mammal, which comprisesadministering an Apo B secretion inhibiting or decreasing amount of saidamide compound or a pharmaceutically acceptable salt thereof to themammal.

[0008] Still further object of this invention is to provide a method forpreventing or treating a disease or condition resulting from elevatedcirculating levels of Apo B in a mammal, such as hyperlipemia,hyperlipidemia, hyperlipoproteinemia, hypercholesterolemia,hypertriglyceridemia, atherosclerosis, pancreatitis, NIDDM, obesity,coronary heart diseases, myocardial infarction, stroke, restenosis andSyndrome X, which method comprises administering an effective amount ofsaid amide compound or a pharmaceutically acceptable salt thereof to themammal.

[0009] The object amide compounds of the present invention are novel andcan be represented by the following general formula (I)

[0010] wherein

[0011] R¹ is hydrogen, lower alkyl, lower alkenyl, halo(lower)alkyl,cyclo(lower)alkyl, lower alkoxy, lower alkylthio, acyl, optionallysubstituted aryl or NR³R⁴, wherein

[0012] R³ and R⁴ are each independently hydrogen, lower alkyl,cyclo(lower)alkyl or acyl; or

[0013] R³, R⁴ and nitrogen atom to which they are attached form anoptionally substituted, saturated or partially saturated N-containingheterocyclic group optionally having one or more oxygen or sulfuratom(s) and optionally having one or two lower alkyl(s);

[0014] R² is hydrogen; or aryl or heteroaryl in which imino group isoptionally protected by amino protective group, each of which isoptionally substituted by cyano, optionally protected amino, lower alkylor heteroaryl substituted by one or more lower alkyl(s);

[0015] X is direct bond or bivalent residue derived from piperazine;

[0016] Y is -(A¹)_(n)-(A²)_(m)-

[0017] wherein

[0018] A¹ is —O—, —NH—, —N(R⁵)—, —CO—, —CH(OH)—, —NH—CO—, —CO—NH—,—CH₂—NH—CO—, —CH₂—CO—NH— or —(CH₂)₂—NH—CO—, wherein R⁵ is aminoprotective group,

[0019] A² is lower alkylene optionally substituted with lower alkyl orheteroaryl, and

[0020] n and m are independently 0 or 1;

[0021] is bivalent residue derived from arene or heteroarene; and

[0022] is bivalent residue derived from arene or heteroarene selectedfrom

[0023] wherein

[0024] Z is N or C(R¹⁰),

[0025] R⁶ is hydrogen, halogen, lower alkyl, lower alkoxy,halo(lower)alkyl, lower alkanoyl, lower alkylthio or —NR⁸R⁹, wherein R⁸and R⁹ are each independently lower alkyl, or R⁸, R⁹ and nitrogen atomto which they are attached form an optionally substituted, saturated orpartially saturated N-containing heterocyclic group optionally havingone or two lower alkyl(s);

[0026] R⁷ is lower alkyl;

[0027] R¹⁰ is the same as R⁶ defined above; and

[0028] q is 1 or 2,

[0029] or a salt thereof.

[0030] The preferred embodiments of the amide compound of the presentinvention is represented by the general formula (I), wherein

[0031] R¹ is hydrogen, lower alkyl, lower alkenyl, halo(lower)alkyl,cyclo(lower)alkyl, lower alkoxy, lower alkylthio, lower alkylsulfonyl orNR³R⁴,

[0032] wherein R³ and R⁴ are each independently hydrogen, lower alkyl,cyclo(lower)alkyl, lower alkanoyl; or

[0033] R³, R⁴ and nitrogen atom to which they are attached form anoptionally substituted, saturated or partially saturated N-containingheterocyclic group selected from

[0034] wherein R¹¹ and R¹² are each independently hydrogen or loweralkyl, and Q is —N(R¹³)—, —O—, —S—, —SO— or —SO₂—, wherein R¹³ ishydrogen or lower alkyl;

[0035] R² is hydrogen, phenyl, pyridinyl, pyrimidinyl, pyrazolyl,thiazolyl, pyrrolyl, triazolyl in which imino group is optionallyprotected by amino protective group, tetrazolyl, furanyl or thienyl,each of which is optionally substituted by cyano, optionally protectedamino, lower alkyl or pyrrolyl substituted by one or more lower alkyl(s);

[0036] is phenylene, pyridinediyl, indolinediyl, isoindolynediyl,3-oxo-2,3-dihydro-1H-indolediyl or 3,4-dihydro-2(1H)-isoquinolinediyl;and

[0037] is bivalent residue derived from arene or heteroarene selectedfrom

[0038] wherein

[0039] Z is N or C(R¹⁰)

[0040] R⁶ is hydrogen, halogen, lower alkyl, lower alkoxy,halo(lower)alkyl, lower alkanoyl, lower alkylthio or —NR⁸R⁹, wherein R⁸and R⁹ are each independently lower alkyl, or

[0041] R⁸, R⁹ and nitrogen atom to which they are attached form anoptionally substituted, saturated or partially saturated N-containingheterocyclic group selected from

[0042] wherein R¹¹, R¹² and Q are as defined above;

[0043] R⁷ is as defined above; and

[0044] q is 1 or 2,

[0045] or a salt thereof.

[0046] Another preferred embodiment of the amide compounds of thepresent invention can be represented by the following general formula(I′)

[0047] wherein

[0048] R² is aryl or heteroaryl, each of which is optionally substitutedby cyano, optionally protected amino, lower alkyl or heteroarylsubstituted by one or more lower alkyl(s);

[0049] R³ and R⁴ are each independently lower alkyl, or R³, R⁴ andnitrogen atom to which they are attached form an optionally substituted,saturated or partially saturated N-containing heterocyclic group;

[0050] R⁶ is hydrogen, halogen, lower alkyl, lower alkoxy,halo(lower)alkyl, lower alkanoyl or —NR⁸R⁹ (wherein R⁸ and R⁹ are eachindependently lower alkyl, or R⁸, R⁹ and nitrogen atom to which they areattached form an optionally substituted, saturated or partiallysaturated N-containing heterocyclic group);

[0051] is bivalent residue derived from arene or heteroarene;

[0052] X is direct bond or bivalent residue derived from piperazine,

[0053] Y is -(A¹)_(n)-(A²)_(m)-

[0054] wherein A¹ is —O—, —NH—, —N(R⁵)—, —CO—, —CH(OH)—, —NH— CO—,—CH₂—NH—CO— or —CH₂—CO—NH—, wherein R⁵ is amino protective group,

[0055] A² is lower alkylene, and

[0056] n and m are independently 0 or 1;

[0057] Z is N or C(R¹⁰) (wherein R¹⁰ is the same as R⁶ defined above),or a salt thereof.

[0058] The preferred embodiments of the amide compound of the presentinvention represented by the general formula (I′) are as follows.

[0059] (1) The compound of the general formula (I′), wherein

[0060] R² is phenyl, pyridinyl, pyrimidinyl, pyrazolyl, thiazolyl,pyrrolyl, triazolyl or tetrazolyl, each of which is optionallysubstituted by cyano, optionally protected amino, lower alkyl orpyrrolyl substituted by one or more lower alkyl(s),

[0061] R³ and R⁴ are each independently lower alkyl, or R³, R⁴ andnitrogen atom to which they are attached form a saturated or partiallysaturated N-containing heterocyclic group selected from

[0062] wherein R¹¹ and R¹² are each independently hydrogen or loweralkyl, and Q is —N(R¹³)—, —O—, —S—, —SO— or —SO₂— wherein R¹³ ishydrogen or lower alkyl;

[0063] R⁶ is hydrogen, halogen, lower alkyl, lower alkoxy,halo(lower)alkyl, lower alkanoyl or —NR⁸R⁹ (wherein R⁸ and R⁹ are eachindependently lower alkyl, or R¹¹, R¹² and nitrogen atom to which theyare attached form a saturated or partially saturated N-containingheterocyclic group selected from

[0064] wherein R¹¹, R¹² and Q are as defined above); and

[0065] is phenylene, pyridinediyl, indolinediyl or isoindolinediyl, or asalt thereof.

[0066] (2) The compound of the general formula (I′), wherein

[0067] R² is phenyl, pyridinyl, pyrimidinyl, pyrazolyl, thiazolyl,pyrrolyl, triazolyl or tetrazolyl, each of which is optionallysubstituted by cyano, optionally protected amino, lower alkyl orpyrrolyl substituted by one or more lower alkyl(s);

[0068] R³ and R⁴ are each independently lower alkyl;

[0069] R⁶ is hydrogen, halogen, lower alkyl, lower alkoxy, loweralkanoyl or halo(lower)alkyl; and

[0070] is phenylene, or a salt thereof.

[0071] (3) The compound of the general formula (I′), wherein

[0072] R² is phenyl, pyridinyl, pyrimidinyl, pyrazolyl, thiazolyl,pyrrolyl, triazolyl or tetrazolyl, each of which is optionallysubstituted by cyano, optionally protected amino, lower alkyl orpyrrolyl substituted by one or more lower alkyl(s);

[0073] R³ and R⁴ are each independently lower alkyl;

[0074] R⁶ is hydrogen, halogen, lower alkyl, lower alkoxy, loweralkanoyl or halo(lower)alkyl; and

[0075] is indolinediyl or isoindolinediyl, or a salt thereof.

[0076] (4) The compound of the general formula (I′), wherein

[0077] R² is phenyl, pyridinyl, pyrimidinyl, pyrazolyl, thiazolyl,pyrrolyl, triazolyl or tetrazolyl, each of which is optionallysubstituted by cyano, optionally protected amino, lower alkyl orpyrrolyl substituted by one or more lower alkyl(s);

[0078] R³, R⁴ and nitrogen atom to which they are attached form asaturated N-containing heterocyclic group of the formula

[0079] wherein R¹¹ and R¹² are each independently hydrogen or loweralkyl;

[0080] R⁶ is hydrogen, halogen, lower alkyl, lower alkoxy, loweralkanoyl or halo(lower)alkyl; and

[0081] is phenylene, or a salt thereof.

[0082] (5) The compound of the general formula (I′), wherein

[0083] R² is phenyl, pyridinyl, pyrimidinyl, pyrazolyl, thiazolyl,pyrrolyl, triazolyl or tetrazolyl, each of which is optionallysubstituted by cyano, optionally protected amino, lower alkyl orpyrrolyl substituted by one or more lower alkyl(s);

[0084] R³, R⁴ and nitrogen atom to which they are attached form asaturated N-containing heterocyclic group of the formula

[0085] wherein R¹¹ and R¹² are each independently hydrogen or loweralkyl;

[0086] R⁶ is hydrogen, halogen, lower alkyl, lower alkoxy, loweralkanoyl or halo(lower)alkyl; and

[0087] is indolinediyl or isoindolinediyl, or a salt thereof.

[0088] Another preferred embodiment of the amide compounds of thepresent invention can be represented by the following general formula(I″)

[0089] wherein

[0090] R² is aryl or heteroaryl, each of which is optionally substitutedby cyano, amino, lower alkyl or heteroaryl substituted by one or morelower alkyl(s);

[0091] R³ and R⁴ are each independently lower alkyl, or R³ , R⁴ andnitrogen atom to which they are attached form an optionally substituted,saturated or partially saturated N-containing heterocyclic group;

[0092] R⁶ is hydrogen, halogen, lower alkyl, lower alkoxy,halo(lower)alkyl or —NR⁸R⁹ (wherein R⁸ and R⁹ are each independentlylower alkyl, or R⁸, R⁹ and nitrogen atom to which they are attached forman optionally substituted, saturated or partially saturated N-containingheterocyclic group);

[0093] is bivalent residue derived from arene or heteroarene;

[0094] X is direct bond or bivalent residue derived from piperazine,

[0095] Y is -(A¹)_(n)-(A²)_(m)-

[0096] wherein A¹ is —O—, —NH—, —N(R⁵)—, —CO— or —NH—CO—,

[0097] wherein R⁵ is amino protective group,

[0098] A² is lower alkylene, and

[0099] n and m are independently 0 or 1; and

[0100] Z is N or C(R¹⁰) (wherein R¹⁰ is the same as R⁶ defined above),or a salt thereof.

[0101] The preferred embodiments of the amide compound of the presentinvention represented by the general formula (I″) are as follows.

[0102] (1) The compound of the general formula (I″), wherein

[0103] R² is phenyl, pyridinyl, pyrimidinyl or thiazolyl, each of whichis optionally substituted with cyano, amino, lower alkyl or pyrrolylsubstituted with one or more lower alkyl;

[0104] R³ and R⁴ are each independently lower alkyl, or R³, R⁴ andnitrogen atom to which they are attached form a saturated or partiallysaturated N-containing heterocyclic group selected from

[0105] wherein R¹¹ and R¹² are each independently hydrogen or loweralkyl, and Q is —N(R¹³)—, —O—, —S—, —SO— or —SO₂— wherein R¹³ ishydrogen or lower alkyl;

[0106] R⁶ is hydrogen, halogen, lower alkyl, lower alkoxy,halo(lower)alkyl or —NR⁸R⁹ (wherein R⁸ and R⁹ are each independentlylower alkyl, or R⁸, R⁹ and nitrogen atom to which they are attached forma saturated or partially saturated N-containing heterocyclic groupselected from

[0107] wherein R¹¹, R¹² and Q are as defined above); and

[0108] is phenylene, pyridinediyl or indolinediyl, or a salt thereof.

[0109] (2) The compound of the general formula (I″), wherein

[0110] R² is phenyl, pyridinyl, pyrimidinyl or thiazolyl, each of whichis optionally substituted with cyano, amino, lower alkyl or pyrrolylsubstituted with one or more lower alkyl;

[0111] R³ and R⁴ are each independently lower alkyl;

[0112] R⁶ is hydrogen, halogen, lower alkyl, lower alkoxy orhalo(lower)alkyl; and

[0113] is phenylene, or a salt thereof.

[0114] (3) The compound of the general formula (I″), wherein

[0115] R² is phenyl, pyridinyl, pyrimidinyl or thiazolyl, each of whichis optionally substituted with cyano, amino, lower alkyl or pyrrolylsubstituted with one or more lower alkyl;

[0116] R³ and R⁴ are each independently lower alkyl;

[0117] R⁶ is hydrogen, halogen, lower alkyl, lower alkoxy orhalo(lower)alkyl; and

[0118] is indolinediyl, or a salt thereof.

[0119] (4) The compound of the general formula (I″), wherein

[0120] R² is phenyl, pyridinyl, pyrimidinyl or thiazolyl, each of whichis optionally substituted with cyano, amino, lower alkyl or pyrrolylsubstituted with one or more lower alkyl;

[0121] R³, R⁴ and nitrogen atom to which they are attached form asaturated N-containing heterocyclic group of the formula

[0122] wherein R¹¹ and R¹² are each independently hydrogen or loweralkyl;

[0123] R⁶ is hydrogen, halogen, lower alkyl, lower alkoxy orhalo(lower)alkyl; and

[0124] is phenylene, or a salt thereof.

[0125] (5) The compound of the general formula (I″), wherein

[0126] R² is phenyl, pyridinyl, pyrimidinyl or thiazolyl, each of whichis optionally substituted with cyano, amino, lower alkyl or pyrrolylsubstituted with one or more lower alkyl;

[0127] R³, R⁴ and nitrogen atom to which they are attached form asaturated N-containing heterocyclic group of the formula

[0128] wherein R¹¹ and R¹² are each independently hydrogen or loweralkyl;

[0129] R⁶ is hydrogen, halogen, lower alkyl, lower alkoxy orhalo(lower)alkyl; and

[0130] is indolinediyl, or a salt thereof.

[0131] The above-mentioned amide compounds represented by the generalformulas (I′) and (I″) are also encompassed in the scope of the compoundrepresented by the general formula (I). Hereinafter “compound (I)” alsoencompasses “compound (I′)” and “compound (I″)”.

[0132] Suitable salts of the object compound (I) may be pharmaceuticallyacceptable salts such as conventional non-toxic salts and include, forexample, a salt with a base or an acid addition salt such as a salt withan inorganic base, for example, an alkali metal salt (e.g., sodium salt,potassium salt, etc.), an alkaline earth metal salt (e.g., calcium salt,magnesium salt, etc.), an ammonium salt; a salt with an organic base,for example, an organic amine salt (e.g., triethylamine salt, pyridinesalt, picoline salt, ethanolamine salt, triethanolamine salt,dicyclohexylamine salt, N,N′-dibenzylethylenediamine salt, etc.); aninorganic acid addition salt (e.g., hydrochloride, hydrobromide,sulfate, phosphate, etc.); an organic carboxylic or sulfonic acidaddition salt (e.g., formate, acetate, trifluoroacetate, maleate,tartrate, citrate, fumarate, methanesulfonate, benzenesulfonate,toluenesulfonate, etc.); and a salt with a basic or acidic amino acid(e.g., arginine, aspartic acid, glutamic acid, etc.).

[0133] In the above and subsequent descriptions of the presentspecification, suitable examples and illustration of the variousdefinitions which the present invention intends to include within thescope thereof are explained in detail as follows.

[0134] The term “lower” is used to intend a group having 1 to 6,preferably 1 to 4, carbon atom(s), unless otherwise provided.

[0135] Suitable “lower alkyl” includes straight or branched alkyl having1 to 6 carbon atom(s), such as methyl, ethyl, propyl, isopropyl, butyl,isobutyl, sec-butyl, tert-butyl, pentyl, tert-pentyl and hexyl, in whichmore preferred one is C₁-C₄ alkyl.

[0136] Suitable “cyclo(lower)alkyl” includes cycloalkyl having 3 to 6carbon atom(s), such as cyclopropyl, cyclobutyl, cyclopentyl andcyclohexyl, in which the preferred one is cyclohexyl.

[0137] Suitable “lower alkenyl” includes straight or branched alkenylhaving 2 to 6 carbon atom(s), such as ethenyl, propenyl, isopropenyl,butenyl, isobutenyl, sec-butenyl, tert-butenyl, pentenyl, tert-pentenyland hexenyl, in which more preferred one is C₂-C₄ alkenyl, and theparticularly preferred one is isopropenyl.

[0138] Suitable “lower alkoxy” includes straight or branched alkoxyhaving 1 to 6 carbon atom(s), such as methoxy, ethoxy, propoxy,isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy,tert-pentyloxy and hexyloxy, in which more preferred one is C₁-C₄alkoxy.

[0139] Suitable “halogen” and “halogen” moiety in the term“halo(lower)alkyl” may be fluorine, bromine, chlorine and iodine.

[0140] Suitable “halo(lower)alkyl” includes straight or branchedhaloalkyl having 1 to 6 carbon atom(s) such as fluoromethyl,bromomethyl, chloromethyl, difluoromethyl, dibromomethyl,dichloromethyl, trifluoromethyl, trichloromethyl and tribromomethyl, inwhich more preferred one is halo(C₁-C₄)alkyl, and the particularlypreferred one is trifluoromethyl.

[0141] Suitable “lower alkylthio” includes alkylthio wherein alkylmoiety is straight or branched alkyl having 1 to 6 carbon atom(s) suchas methylthio, ethylthio, propylthio, isopropylthio, butylthio,isobutylthio, sec-butylthio, tert-butylthio, pentylthio, tert-pentylthioand hexylthio, in which more preferred one is C₁-C₄ alkylthio, and theparticularly preferred one is methylthio.

[0142] Suitable “lower alkylene” includes straight or branched alkylenehaving 1 to 6 carbon atom(s), such as methylene, ethylene, trimethylene,tetramethylene, propylene, ethylidene and propylidene, in which morepreferred one is C₁-C₃ alkylene, and the particularly preferred ones aremethylene and ethylene.

[0143] Suitable examples of “amino protective group” include acyl suchas lower alkanoyl (e.g., formyl, acetyl, etc.), lower alkoxycarbonyl,mono(or di or tri)phenyl(lower)alkoxycarbonyl, and a conventionalprotective group such as mono(or di or tri)aryl(lower)alkyl, forexample, mono(or di or tri)phenyl(lower)alkyl.

[0144] Suitable “acyl” includes “lower alkanoyl”, “loweralkoxycarbonyl”, “aryl(lower)alkoxycarbonyl”, “carbamoyl”,“N-(lower)alkylcarbamoyl”, “N,N-di(lower)alkylcarbamoyl” and “loweralkylsulfonyl”.

[0145] Suitable “lower alkanoyl” includes alkanoyl having 1 to 6 carbonatom(s) such as formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl,isovaleryl, pivaloyl and hexanoyl, in which more preferred one is C₁-C₄alkanoyl.

[0146] Suitable “N-(lower)alkylcarbamoyl” includes N-alkylcarbamoylwherein alkyl moiety is alkyl having 1 to 6 carbon atom(s) such asN-methylcarbamoyl, N-ethylcarbamoyl, N-isopentylcarbamoyl andN-hexylcarbamoyl.

[0147] Suitable “N,N-di(lower)alkylcarbamoyl” includesN,N-dialkylcarbamoyl wherein two alkyl moieties may be same ordifferent, such as N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl,N-methyl-N-ethylcarbamoyl, N-pentyl-N-hexylcarbamoyl, etc.

[0148] Suitable “lower alkylsulfonyl” includes alkylsulfonyl whereinalkyl moiety is alkyl having 1 to 6 carbon atom(s) such asmethylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl,butylsulfonyl, isobutylsulfonyl, sec-butylsulfonyl, tert-butylsulfonyl,pentylsulfonyl, tert-pentylsulfonyl and hexylsulfonyl, in which thepreferred one is C₁-C₄ alkylsulfonyl.

[0149] Suitable “lower alkoxycarbonyl” includes alkoxycarbonyl whereinalkoxy moiety has 1 to 6 carbon atom(s) such as methoxycarbonyl,ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl,isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl,pentyloxycarbonyl, tert-pentyloxycarbonyl and hexyloxycarbonyl, in whichmore preferred one is alkoxycarbonyl wherein alkoxy moiety has 1 to 4carbon atom(s).

[0150] Suitable “aryl(lower)alkoxycarbonyl” includes “mono(or di ortri)phenyl(lower)alkoxycarbonyl”, etc. The “mono(or di ortri)phenyl(lower)alkoxycarbonyl” includes mono(or di ortri)phenylalkoxycarbonyl wherein alkoxy moiety has 1 to 6 carbon atom(s)such as benzyloxycarbonyl and phenethyloxycarbonyl. Suitable “mono(or dior tri)phenyl(lower)alkyl” includes mono(or di or tri)phenyl(C₁-C₆)alkylsuch as benzyl, benzhydryl and trityl.

[0151] Suitable “saturated or partially saturated N-containingheterocyclic group” includes a saturated or partially saturated 4 to8-membered (more preferably 5 to 7-membered) heteromonocyclic groupcontaining 1 or 2 nitrogen atom(s) and optionally containing oxygen atomor sulfur atom, such as pyrrolidinyl, piperidinyl, piperazinyl,morpholinyl, thiomorpholinyl, hexahydroazepinyl and tetrahydropyridinyl.

[0152] “Saturated or partially saturated N-containing heterocyclicgroup” is optionally substituted by suitable substituent(s) such aslower alkyl and oxo.

[0153] Suitable “aryl” includes C₆-C₁₂ aryl. “Aryl” includes fusedcarbocyclic group wherein benzene ring is fused with a saturated orunsaturated carbon ring.

[0154] Suitable examples of “aryl” include phenyl, naphthyl, indenyl andindanyl, in which more preferred one is phenyl.

[0155] Suitable “heteroaryl” includes 5 to 10-membered aromaticheteromonocyclic or fused heterocyclic group containing 1 to 4heteroatom(s) selected from sulfur atom, oxygen atom and nitrogen atom.“Heteroaryl” includes fused heterocyclic group wherein benzene ring isfused with a saturated or unsaturated heterocyclic ring.

[0156] Suitable examples of “heteroaryl” include pyridinyl, pyrimidinyl,pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl,tetrazolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl,furanyl, thienyl, indolyl, isoindolyl, indolizinyl, indazolyl,benzimidazolyl, benzotriazolyl, quinolyl, isoquinolyl, phthalazinyl,quinoxalinyl, quinazolinyl, cinnolinyl, benzofuranyl, benzothienyl,benzoxazolyl, benzothiazolyl, benzimidazolyl, indolinyl, isoindolinyl,tetrahydroquinolinyl and tetrahydroisoquinolinyl.

[0157] Suitable “bivalent residue derived from arene” includes C₆-C₁₂arylene. “Bivalent residue derived from arene” include bivalent fusedcarbocyclic group wherein benzene ring is fused with a saturated orunsaturated carbon ring.

[0158] Suitable examples of “bivalent residue derived from arene”include phenylene, naphthylene, indenediyl and indandiyl, in which morepreferred one is phenylene.

[0159] Suitable “bivalent residue derived from heteroarene” includesbivalent 5 to 10-membered aromatic heteromonocyclic or fusedheterocyclic group containing 1 to 4 heteroatom(s) selected from sulfuratom, oxygen atom and nitrogen atom. “Bivalent residue derived fromheteroarene” includes bivalent fused heterocyclic group wherein benzenering is fused with a saturated or unsaturated heterocyclic ring.

[0160] Suitable examples of “bivalent residue derived from heteroarene”include pyridinediyl, pyrimidinediyl, pyrazinediyl, pyridazinediyl,pyrrolediyl, imidazolediyl, pyrazolediyl, triazolediyl, tetrazolediyl,thiazolediyl, isothiazolediyl, thiadiazolediyl, oxazolediyl,isoxazolediyl, furandiyl, thiophenediyl, indolediyl, isoindolediyl,indolizinediyl, indazolediyl, benzimidazolediyl, benzotriazolediyl,quinolinediyl, isoquinolinediyl, phthalazinediyl, quinoxalinediyl,quinazolinediyl, cinnolinediyl, benzofurandiyl, benzothiophenediyl,benzoxazolediyl, benzothiazolediyl, benzimidazolediyl, indolinediyl,isoindolinediyl, tetrahydroquinolinediyl and tetrahydroisoquinolinediyl.

[0161] Suitable examples of “carboxy protective group” include loweralkyl (e.g., methyl, ethyl, tert-butyl, etc.), mono(or di ortri)phenyl(lower)alkyl optionally substituted by nitro (e.g., benzyl,4-nitrobenzyl, benzhydryl, trityl, etc.) and loweralkylcarbonyloxy(lower)alkyl (e.g., pivaloyloxymethyl).

[0162] Preferable examples of “optionally substituted, saturated orpartially saturated N-containing heterocyclic group” include groups ofthe following formulas:

[0163] wherein R¹¹ and R¹² are each independently hydrogen or loweralkyl, and Q is —N(R¹³)—, —O—, —S—, —SO— or —SO₂— wherein R¹³ ishydrogen or lower alkyl.

[0164] Preferable example of “aryl” at R² is phenyl.

[0165] Preferable examples of “heteroaryl” at R² include 5 or 6-memberedaromatic heteromonocyclic group containing 1 to 4 nitrogen atom(s) suchas pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl,pyrazolyl, triazolyl, tetrazolyl and thiazolyl, and more preferablypyridinyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl and thiazolyl,particularly preferably, pyridinyl.

[0166] Preferable examples of “heteroaryl substituted by one or morelower alkyl(s)” include pyrrolyl substituted by one or more loweralkyl(s), and more preferably 2,5-dimethyl-1H-pyrrol-1-yl.

[0167] Preferable example of “bivalent residue derived from arene” at

[0168] is phenylene.

[0169] Preferable examples of “bivalent residue derived fromheteroarene” at

[0170] include bivalent 5 or 6-membered aromatic heteromonocyclic groupcontaining 1 to 4 nitrogen atom(s) such as pyridinediyl, pyrimidinediyl,pyrazinediyl, pyridazinediyl, pyrrolediyl, imidazolediyl, pyrazolediyl,triazolediyl and tetrazolediyl; and bivalent 8 to 10-membered fusedheterocyclic group containing 1 to 4 nitrogen atom(s) wherein benzenering is fused with a saturated or unsaturated heterocyclic ring such asindolinediyl, isoindolinediyl, tetrahydroquinolinediyl andtetrahydroisoquinolinediyl.

[0171] More preferably, “bivalent residue derived from heteroarene” at

[0172] is pyridinediyl, indolinediyl or isoindolinediyl.

[0173] Particularly preferable examples of “bivalent residue derivedfrom arene or heteroarene” at

[0174] include

[0175] Preferable example of “bivalent residue derived from piperazine”at X is 1,4-piperazinediyl.

[0176] Preferable examples of a group represented by Y include—NH—CO—CH₂—, —N(R⁵)—(CH₂)₂—, —O—CH₂—, —CH₂—, —CO—CH₂—, —CH(OH)—,—O—(CH₂)₂—, —(CH₂)₂—, —CO—(CH₂)₂—, —CH(OH)—(CH₂)₂—, —(CH₂)₃—,—CH₂—CO—NH—, —CH₂—NH—CO—, —NH(CH₂)₂—, —CONH—, —(CH₂)₂—NH—CO—, —CONHCH₂—,—CONH(CH₂)₂—, —NHCOCH(CH₃)—, —CONHCH(CH₃)— and

[0177] and more preferably, —NH—CO—CH₂—, —N(R⁵)—(CH₂)₂—, —O—CH₂—, —CH₂—,—CO—CH₂—, —CH(OH)—, —O(CH₂)₂—, —NH(CH₂)₂—, —CONH—, —CONHCH₂—,—CONH(CH₂)₂—, —NHCOCH(CH₃)— and —CONHCH(CH₃)—.

[0178] The object compound (I) of the present invention can be preparedby the following processes.

[0179] Process (1)

[0180] Process (2)

[0181] Process (3)

[0182] Process (4)

[0183] Process (5)

[0184] Process (6)

[0185] Process (7)

[0186] Process (8)

[0187] Process (9)

[0188] Process (10)

[0189] Process (11)

[0190] wherein R¹, R², R³, R⁴, R⁵,

[0191] X, Y, Z, A² and m are as defined above,

[0192] X¹ is leaving group such as halogen (e.g., chlorine, bromine orfluorine) and trifluoromethanesulfonyloxy,

[0193] W is halogen (e.g., chlorine, bromine or fluorine),

[0194] V is CH or nitrogen atom,

[0195] R^(2a) is aryl or heteroaryl, each of which is substituted byprotected amino,

[0196] R^(2b) is aryl or heteroaryl, each of which is substituted byamino, and

[0197] R¹⁷ is amino protective group.

[0198] The starting compounds can be prepared by the following processesor by the method of Preparation mentioned below or by a process known inthe art for preparing their structurally analogous compounds.

[0199] Process (A)

[0200] Process (B)

[0201] Process (C)

[0202] Process (D)

[0203] Process (E)

[0204] Process (F)

[0205] Process (G)

[0206] Process (H)

[0207] Process (I)

[0208] Process (J)

[0209] Process (K)

[0210] Process (L)

[0211] Process (M)

[0212] Process (N)

[0213] wherein R¹, R², R³, R⁴ ,

[0214] X, Y, Z, A², m and X¹ are as defined above,

[0215] W and W′ are each halogen such as fluorine, chlorine, bromine,etc.,

[0216] R¹⁴ is carboxy protective group, and

[0217] R¹⁵ and R¹⁶ are each amino protective group.

[0218] The processes for preparing the object and starting compounds areexplained in detail in the following.

[0219] Process (1)

[0220] The compound (I) or a salt thereof can be prepared by reactingthe compound (II) or its reactive derivative at the carboxy group, or asalt thereof with the compound (III) or its reactive derivative at theamino group, or a salt thereof.

[0221] Suitable reactive derivative of the compound (III) includesSchiff's base type imino or its tautomeric enamine type isomer formed bythe reaction of the compound (III) with a carbonyl compound such asaldehyde, ketone or the like; a silyl derivative formed by the reactionof the compound (III) with a silyl compound such asN,O-bis(trimethylsilyl)acetamide, N-trimethylsilylacetamide or the like;a derivative formed by the reaction of the compound (III) withphosphorus trichloride or phosgene.

[0222] Suitable reactive derivative of the compound (II) includes anacid halide, an acid anhydride and an activated ester. The suitableexample may be an acid chloride; an acid azide; a mixed acid anhydridewith an acid such as substituted phosphoric acid (e.g.,dialkylphosphoric acid, phenylphosphoric acid, diphenylphosphoric acid,dibenzylphosphoric acid, halogenated phosphoric acid, etc.),dialkylphosphorous acid, sulfurous acid, thiosulfuric acid,alkanesulfonic acid (e.g., methanesulfonic acid, ethanesulfonic acid,etc.), sulfuric acid, alkylcarbonic acid, aliphatic carboxylic acid(e.g., pivalic acid, pentanoic acid, isopentanoic acid, 2-ethylbutyricacid, trichloroacetic acid, etc.); aromatic carboxylic acid (e.g.,benzoic acid, etc.); a symmetrical acid anhydride; an activated amidewith imidazole, 4-substituted imidazole, dimethylpyrazole, triazole ortetrazole; an activated ester (e.g., cyanomethyl ester, methoxymethylester, dimethyliminomethyl[(CH₃)₂N⁺═CH—]ester, vinyl ester, propargylester, p-nitrophenyl ester, 2,4-dinitrophenyl ester, trichlorophenylester, pentachlorophenyl ester, mesylphenyl ester, phenylazophenylester, phenyl thioester, p-nitrophenyl thioester, p-cresyl thioester,carboxymethyl thioester, pyranyl ester, pyridinyl ester, piperidylester, 8-quinolyl thioester, etc.); or an ester with an N-hydroxycompound (e.g., N,N-dimethylhydroxylamine, 1-hydroxy-2-(1H)-pyridone,N-hydroxysuccinimide, N-hydroxybenzotriazole, N-hydroxyphthalimide,1-hydroxy-6-chloro-1H-benzotriazole, etc.). These reactive derivativescan optionally be selected from them according to the kind of thecompound (II) to be used.

[0223] The reaction is usually carried out in a conventional solventsuch as water, acetone, dioxane, acetonitrile, chloroform, methylenechloride, ethylene dichloride, tetrahydrofuran, ethyl acetate,N,N-dimethylformamide, pyridine or any other organic solvents which donot adversely affect the reaction, or a mixture thereof.

[0224] When the compound (II) is used in free acid form or its salt formin the reaction, the reaction is preferably carried out in the presenceof a conventional condensing agent such asN,N′-dicyclohexylcarbodiimide;N-cyclohexyl-N′-morpholinoethylcarbodiimide;N-cyclohexyl-N′-(4-diethylaminocyclohexyl)carbodiimide;N,N′-diisopropylcarbodiimide;N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide;N,N-carbonyl-bis-(2-methylimidazole);pentamethyleneketene-N-cyclohexylimine;diphenylketene-N-cyclohexylimine; ethoxyacetylene;1-alkoxy-1-chloroethylene; trialkyl phosphite; isopropyl polyphosphate;phosphorus oxychloride(phosphoryl chloride); phosphorus trichloride;thionyl chloride; oxalyl chloride; triphenylphosphine;2-ethyl-7-hydroxybenzisoxazolium salt;2-ethyl-5-(m-sulfophenyl)isoxazolium hydroxide intramolecular salt;1-(p-chlorobenzenesulfonyloxy)-6-chloro-1H-benzotriazole; so-calledVilsmeier reagent prepared by the reaction of N,N-dimethylformamide withthionyl chloride, phosgene, phosphorus oxychloride, etc.; or the like.

[0225] The reaction may also be carried out in the presence of anorganic or inorganic base such as an alkali metal bicarbonate,tri(lower)alkylamine, pyridine, N-(lower)alkylmorpholine,N,N-di(lower)alkylbenzylamine, or the like.

[0226] The reaction temperature is not critical, and the reaction isusually carried out under cooling to heating.

[0227] Process (2)

[0228] The compound (I)-1 or a salt thereof can be prepared by reactingthe compound (IV) or its reactive derivative at the amino group, or asalt thereof with the compound (V) or its reactive derivative at thecarboxy group, or a salt thereof.

[0229] This reaction can be carried out in the same manner as in theaforementioned Process (1), and therefore the reagents to be used andthe reaction conditions (e.g., solvent, reaction temperature, etc.) canbe referred to those of Process (1).

[0230] Process (3)

[0231] The compound (I)-3 or a salt thereof can be prepared by reactingthe compound (VI) or a salt thereof with the compound (VII) or a saltthereof.

[0232] The reaction is usually carried out in a conventional solventsuch as tetrahydrofuran, dioxane, toluene, methylene chloride, ethylenedichloride, chloroform, N,N-dimethylformamide, N,N-dimethylacetamide orany other organic solvents which do not adversely affect the reaction,or a mixture thereof.

[0233] The reaction temperature is not critical, and the reaction isusually carried out under cooling to warming.

[0234] Process (4)

[0235] The compound (I)-5 or a salt thereof can be prepared bysubjecting the compound (I)-4 or a salt thereof to elimination reactionof the amino protective group.

[0236] Suitable method of this elimination reaction includesconventional one such as hydrolysis, reduction and the like.

[0237] (i) For Hydrolysis:

[0238] The hydrolysis is preferably carried out in the presence of abase or an acid including Lewis acid.

[0239] Suitable base includes an inorganic base and an organic base suchas an alkali metal [e.g., sodium, potassium, etc.], an alkaline earthmetal [e.g., magnesium, calcium, etc.], the hydroxide or carbonate orhydrogencarbonate thereof, trialkylamine [e.g., trimethylamine,triethylamine, etc.], picoline, 1,5-diazabicyclo[4.3.0]non-5-ene, or thelike.

[0240] Suitable acid includes an organic acid [e.g., formic acid, aceticacid, propionic acid, trichloroacetic acid, trifluoroacetic acid, etc.],and an inorganic acid [e.g., hydrochloric acid, hydrobromic acid,sulfuric acid, hydrogen chloride, hydrogen bromide, etc.].

[0241] The elimination using Lewis acid such as trihaloacetic acid[e.g., trichloroacetic acid, trifluoroacetic acid, etc.], or the like ispreferably carried out in the presence of cation trapping agents [e.g.,anisole, phenol, etc.]. This reaction is usually carried out withoutsolvent.

[0242] The reaction may be carried out in a conventional solvent such aswater, alcohol (e.g., methanol, ethanol, isopropyl alcohol, etc.),tetrahydrofuran, dioxane, toluene, methylene chloride, ethylenedichloride, chloroform, N,N-dimethylformamide, N,N-dimethylacetamide orany other organic solvents which do not adversely affect the reaction,or a mixture thereof.

[0243] The reaction temperature is not critical and the reaction isusually carried out under cooling to warming.

[0244] (ii) For Reduction:

[0245] Reduction is carried out in a conventional manner, includingchemical reduction and catalytic reduction.

[0246] Suitable reducing reagent to be used in chemical reduction arehydrides (e.g., hydrogen iodide, hydrogen sulfide, lithium aluminumhydride, sodium borohydride, sodium cyanoborohydride, etc.), or acombination of a metal (e.g., tin, zinc, iron, etc.) or metalliccompound (e.g., chromium chloride, chromium acetate, etc.) and anorganic acid or inorganic acid (e.g., formic acid, acetic acid,propionic acid, trifluoroacetic acid, p-toluenesulfonic acid,hydrochloric acid, hydrobromic acid, etc.).

[0247] Suitable catalysts to be used in catalytic reduction areconventional ones such as platinum catalysts (e.g., platinum plate,spongy platinum, platinum black, colloidal platinum, platinum oxide,platinum wire, etc.), palladium catalysts (e.g., spongy palladium,palladium black, palladium oxide, palladium on carbon, palladiumhydroxide on carbon, colloidal palladium, palladium on barium sulfate,palladium on barium carbonate, etc.), nickel catalysts (e.g., reducednickel, nickel oxide, Raney nickel, etc.), cobalt catalysts (e.g.,reduced cobalt, Raney cobalt, etc.), iron catalysts (e.g., reduced iron,Raney iron, Ullman iron, etc.), and the like.

[0248] The reduction is usually carried out in a conventional solventsuch as water, alcohol (e.g., methanol, ethanol, isopropyl alcohol,etc.), tetrahydrofuran, dioxane, toluene, methylene chloride, ethylenedichloride, chloroform, N,N-dimethylformamide, N,N-dimethylacetamide orany other organic solvents which do not adversely affect the reaction,or a mixture thereof.

[0249] Additionally, in case that the above-mentioned acids to be usedin chemical reduction are in a liquid state, they can also be used as asolvent.

[0250] The reaction temperature of this reduction is not critical andthe reaction is usually carried out under cooling to warming.

[0251] Process (5)

[0252] The compound (I)-7 or a salt thereof can be prepared bysubjecting the compound (I)-6 or a salt thereof to elimination reactionof the amino protective group.

[0253] This reaction can be carried out in the same manner as in theaforementioned Process (4), and therefore the reagents to be used andthe reaction conditions (e.g., solvent, reaction temperature, etc.) canbe referred to those of Process (4).

[0254] Process (6)

[0255] The compound (I)-9 can be prepared by subjecting the compound(I)-8 to reduction using a suitable reducing agent.

[0256] Suitable reducing agents to be used in the reduction are hydrides(e.g., sodium borohydride, sodium cyanoborohydride, lithium aluminumhydride, etc.).

[0257] The reduction is usually carried out in a conventional solventsuch as water, alcohol (e.g., methanol, ethanol, isopropyl alcohol,etc.), tetrahydrofuran, dioxane, toluene, methylene chloride, ethylenedichloride, chloroform, N,N-dimethylformamide, N,N-dimethylacetamide orany other organic solvents which do not adversely affect the reaction,or a mixture thereof.

[0258] The reaction temperature is not critical, and the reaction isusually carried out under cooling to warming.

[0259] Process (7)

[0260] The compound (I)-10 can be prepared by subjecting the compound(I)-9 to catalytic hydrogenation in the presence of an acid.

[0261] Suitable catalysts to be used in the catalytic hydrogenation areconventional ones such as platinum catalysts (e.g., platinum plate,spongy platinum, platinum black, colloidal platinum, platinum oxide,platinum wire, etc.), palladium catalysts (e.g., spongy palladium,palladium black, palladium oxide, palladium on carbon, palladiumhydroxide on carbon, colloidal palladium, palladium on barium sulfate,palladium on barium carbonate, etc.), and the like.

[0262] Suitable acid to be used in the catalytic hydrogenation includeshydrochloric acid, hydrogen chloride, and the like.

[0263] The hydrogenation is usually carried out in a conventionalsolvent such as water, alcohol (e.g., methanol, ethanol, isopropylalcohol, etc.), tetrahydrofuran, dioxane, toluene, methylene chloride,ethylene dichloride, chloroform, N,N-dimethylformamide,N,N-dimethylacetamide or any other organic solvents which do notadversely affect the reaction, or a mixture thereof.

[0264] The reaction temperature is not critical, and the reaction isusually carried out under cooling to warming.

[0265] Process (8)

[0266] The compound (I)-11 or a salt thereof can be prepared by reactingthe compound (XXII) or a salt thereof with the compound (XXVI) or a saltthereof.

[0267] This reaction is generally carried out in the presence of anorganic or inorganic base such as potassium tert-butoxide, sodiumbicarbonate, sodium hydride, triethylamine, etc., and in a solvent suchas N,N-dimethylformamide, chloroform, diethyl ether, dioxane,tetrahydrofuran, acetonitrile, etc., or any other organic solvents whichdo not adversely affect the reaction, or a mixture thereof.

[0268] The reaction temperature is not critical, and the reaction isusually carried out under cooling to warming.

[0269] Process (9)

[0270] The compound (I)-12 or a salt thereof can be prepared by reactingthe compound (XXV) or a salt thereof with the compound (XXVII) or a saltthereof.

[0271] The reaction is usually carried out in the presence of a reducingagent such as sodium triacetoxyborohydride, sodium cyanoborohydride,etc., and in a conventional solvent such as chloroform, ethylenechloride, acetonitrile, diethyl ether, tetrahydrofuran, methanol, etc.,or any other organic solvents which do not adversely affect thereaction, or a mixture thereof.

[0272] The reaction temperature is not critical, and the reaction isusually carried out under cooling to warming.

[0273] Process (10)

[0274] The compound (I)-13 or a salt thereof can be prepared by reactingthe compound (XXVI) with the compound (XXVII) in the presence of anorganic base such as triethylamine, pyridine, etc., and in aconventional solvent such as tetrahydrofuran, chloroform, diethyl ether,N,N-dimethylformamide, etc., or any other organic solvents which do notadversely affect the reaction, or a mixture thereof.

[0275] The reaction temperature is not critical, and the reaction isusually carried out under cooling to warming.

[0276] Process (11)

[0277] The compound (I)-14 or a salt thereof can be prepared bysubjecting the compound (I)-13 or a salt thereof to elimination reactionof the amino protective group.

[0278] This reaction can be carried out in the same manner as theelimination reaction of the amino protective group in the aforementionedProcess (4), and therefore the reagents to be used and the reactionconditions (e.g., solvent, reaction temperature, etc.) can be referredto those of Process (4).

[0279] Process (A)

[0280] The compound (IX)-1 or a salt thereof can be prepared by reactingthe compound (VIII) or a salt thereof with the compound (VII) or a saltthereof.

[0281] This reaction can be carried out in the same manner as in theaforementioned Process (3), and therefore the reagents to be used andthe reaction conditions (e.g., solvent, reaction temperature, etc.) canbe referred to those of Process (3).

[0282] Process (B)

[0283] The compound (II) or a salt thereof can be prepared by subjectingthe compound (IX) or a salt thereof to elimination reaction of thecarboxy protective group.

[0284] Suitable method of this elimination reaction includesconventional one such as hydrolysis, reduction and the like.

[0285] This reaction can be carried out in the same manner as theelimination reaction of the amino protective group in the aforementionedProcess (4), and therefore the reagents to be used and the reactionconditions (e.g., solvent, reaction temperature, etc.) can be referredto those of Process (4).

[0286] Process (C)

[0287] The compound (XI)-1 or a salt thereof can be prepared by reactingthe compound (X) or its reactive derivative at the amino group, or asalt thereof with the compound (V) or its reactive derivative at thecarboxy group, or a salt thereof.

[0288] This reaction can be carried out in the same manner as in theaforementioned Process (1), and therefore the reagents to be used andthe reaction conditions (e.g., solvent, reaction temperature, etc.) canbe referred to those of Process (1).

[0289] Process (D)

[0290] The compound (III) can be prepared by subjecting the compound(XI) to reduction.

[0291] Suitable method of the reduction is catalytic hydrogenation.

[0292] Suitable catalysts to be used in the catalytic hydrogenation areconventional ones such as platinum catalysts (e.g., platinum plate,spongy platinum, platinum black, colloidal platinum, platinum oxide,platinum wire, etc.), palladium catalysts (e.g., spongy palladium,palladium black, palladium oxide, palladium on carbon, palladiumhydroxide on carbon, colloidal palladium, palladium on barium sulfate,palladium on barium carbonate, etc.), and the like.

[0293] The hydrogenation is usually carried out in a conventionalsolvent such as water, alcohol (e.g., methanol, ethanol, isopropylalcohol, etc.), tetrahydrofuran, dioxane, toluene, methylene chloride,ethylene dichloride, chloroform, N,N-dimethylformamide,N,N-dimethylacetamide or any other organic solvents which do notadversely affect the reaction, or a mixture thereof.

[0294] The reaction temperature is not critical, and the reaction isusually carried out under cooling to warming.

[0295] Process (E)

[0296] The compound (XIV) or a salt thereof can be prepared by reactingthe compound (XII) or its reactive derivative at the carboxy group, or asalt thereof with the compound (XIII) or its reactive derivative at theamino group, or a salt thereof.

[0297] This reaction can be carried out in the same manner as in theaforementioned Process (1), and therefore the reagents to be used andthe reaction conditions (e.g., solvent, reaction temperature, etc.) canbe referred to those of Process (1).

[0298] Process (F)

[0299] The compound (XV)-1 or a salt thereof can be prepared by reactingthe compound (XIV) or a salt thereof with the compound (VII) or a saltthereof.

[0300] This reaction can be carried out in the same manner as in theaforementioned Process (3), and therefore the reagents to be used andthe reaction conditions (e.g., solvent, reaction temperature, etc.) canbe referred to those of Process (3).

[0301] Process (G)

[0302] The compound (IV) or a salt thereof can be prepared by subjectingthe compound (XV) or a salt thereof to elimination reaction of the aminoprotective group.

[0303] This reaction can be carried out in the same manner as in theaforementioned Process (4), and therefore the reagents to be used andthe reaction conditions (e.g., solvent, reaction temperature, etc.) canbe referred to those of Process (4).

[0304] Process (H)

[0305] The compound (VI) or a salt thereof can be prepared by reactingthe compound (XII) or its reactive derivative at the carboxy group, or asalt thereof with the compound (III) or its reactive derivative at theamino group, or a salt thereof.

[0306] This reaction can be carried out in the same manner as in theaforementioned Process (1), and therefore the reagents to be used andthe reaction conditions (e.g., solvent, reaction temperature, etc.) canbe referred to those of Process (1).

[0307] Process (I)

[0308] The compound (IX)-2 or the salt thereof can be prepared byreacting the compound (XVI) or a salt thereof with the compound (XVII)or a salt thereof.

[0309] This reaction is usually carried out in accordance with aconventional method.

[0310] This methylation is preferably carried out without a solvent, orin an any solvent which do not adversely affect the reaction, or amixture thereof.

[0311] The reaction temperature is not critical, and the reaction isusually carried out under warming to heating.

[0312] Process (J)

[0313] The compound (XX) or the salt thereof can be prepared by reactingthe compound (XVIII) or a salt thereof with the compound (XIX).

[0314] This reaction is usually carried out in accordance with aconventional method.

[0315] This reductive methylation is usually carried out in the presenceof catalysts, and the suitable catalysts to be used in this reaction areconventional ones such as platinum catalysts (e.g., platinum plate,spongy platinum, platinum black, colloidal platinum, platinum oxide,platinum wire, etc.), palladium catalysts (e.g., spongy palladium,palladium black, palladium oxide, palladium on carbon, palladiumhydroxide on carbon, colloidal palladium, palladium on barium sulfate,palladium on barium carbonate, etc.), and the like.

[0316] This reaction is preferably in a conventional solvent such aswater, alcohol (e.g., methanol, ethanol, isopropyl alcohol, etc.),tetrahydrofuran, dioxane, toluene, methylene chloride, ethylenedichloride, chloroform, N,N-dimethylformamide, N,N-dimethylacetamide orany other organic solvents which do not adversely affect the reaction,or a mixture thereof.

[0317] The reaction temperature is not critical, and the reaction isusually carried out under cooling to warming.

[0318] Process (K)

[0319] The compound (IX)-3 can be synthesized by functionaltransformation of hydroxyl group to carboxyl group that comprisessuccessive trifluoromethanesulfonylation and esterification, which isobvious to the person skilled in the organic chemistry, exemplified bythe methods disclosed in e.g. Preparation 72 and Preparation 73mentioned later or the similar manner thereby.

[0320] Process (L)

[0321] The compound (XXII) or the salt thereof can be prepared byreacting the compound (IV) or a salt thereof with the compound (XXI).

[0322] This reaction can be carried out in the same manner as in theaforementioned Process (10), and therefore the reagents to be used andthe reaction conditions (e.g., solvent, reaction temperature, etc.) canbe referred to those of Process (10).

[0323] Process (M)

[0324] The compound (XXIV) or a salt thereof can be prepared by reactingthe compound (XXIII) or its reactive derivative at the amino group, or asalt thereof with the compound (II) or its reactive derivative at thecarboxy group, or a salt thereof.

[0325] This reaction can be carried out in the same manner as in theaforementioned Process (1), and therefore the reagents to be used andthe reaction conditions (e.g., solvent, reaction temperature, etc.) canbe referred to those of Process (1).

[0326] Process (N)

[0327] The compound (XXV) or a salt thereof can be prepared bysubjecting the compound (XXIV) or a salt thereof to elimination reactionof the amino protective group of the nitrogen atom on the pipirazinering.

[0328] This reaction can be carried out in the same manner as in theaforementioned Process (4), and therefore the reagents to be used andthe reaction conditions (e.g., solvent, reaction temperature, etc.) canbe referred to those of Process (4).

[0329] Suitable salts of the starting compounds and their reactivederivatives in Processes (1) to (11) and (A) to (N) can be referred tothe ones as exemplified for the compound (I).

[0330] The compounds obtained by the above processes can be isolated andpurified by a conventional method such as pulverization,recrystallization, column chromatography, reprecipitation, or the like.

[0331] It is to be noted that the compound (I) and the other compoundsmay include one or more stereoisomer(s) such as optical isomer(s) andgeometrical isomer(s) due to asymmetric carbon atom(s) and doublebond(s), and all of such isomers and mixtures thereof are includedwithin the scope of this invention.

[0332] The object compounds (I) and pharmaceutically acceptable saltsthereof include solvates [e.g., enclosure compounds (e.g., hydrate,etc.)].

[0333] The object compounds (I) and pharmaceutically acceptable saltsthereof possess a strong inhibitory activity on the secretion of Apo B.

[0334] Accordingly, the object compounds (I) and pharmaceuticallyacceptable salts thereof are useful as an Apo B secretion inhibitor.

[0335] The object compounds (I) and pharmaceutically acceptable saltsthereof are useful as a medicament for the prophylaxis or treatment ofdiseases or conditions resulting from elevated circulating levels of ApoB such as hyperlipemia, hyperlipidemia, hyperlipoproteinemia,hypoalphalipoproteinemia, hypercholesterolemia, hypertriglyceridemia,atherosclerosis, pancreatitis, non-insulin dependent diabetes mellitus(NIDDM), obesity, coronary heart diseases, myocardial infarction,stroke, restenosis and Syndrome X.

[0336] The present invention therefore provides a method for inhibitingor decreasing Apo B secretion in a mammal, in particular in human, whichcomprises administering an Apo B secretion inhibiting or decreasingamount of a compound of formula (I) or a pharmaceutically acceptablesalt thereof to the mammal.

[0337] The present invention also provides a method for preventing ortreating diseases or conditions resulting from elevated circulatinglevels of Apo B in a mammal, in particular in human, which comprisesadministering an effective amount of a compound of formula (I) or apharmaceutically acceptable salt thereof to the mammal.

[0338] The object compounds (I) and pharmaceutical acceptable saltsthereof are also useful in reducing intestinal fat absorption andreducing food intake for the prophylaxis or treatment of obesity.Furthermore, the object compounds (I) and pharmaceutical acceptablesalts thereof possess an inhibitory activity on the lipid transfer ofmicrosomal triglyceride transfer protein (MTP).

[0339] In order to illustrate the usefulness of the object compound (I),the pharmacological test result of the compound (I) is shown in thefollowing.

[0340] Test Compounds:

[0341]2-(dimethylamino)-4-methyl-N-(4-{[2-(2-pyridinyl)ethyl]amino}phenyl)benzamide(Example 42)

[0342]2-(4-methyl-1-piperidinyl)-N-(4-{[2-(2-pyridinyl)ethyl]amino}phenyl)nicotinamide(Example 54)

[0343]2-(dimethylamino)-4-methyl-N-(4-{[2-(1H-pyrazol-1-yl)ethyl]amino}phenyl)benzamide(Example 183)

[0344]6-methyl-2-(4-methyl-1-piperidinyl)-N-{4-[(1H-pyrazol-1-ylacetyl)amino]phenyl}nicotinamide(Example 193)

[0345]6-methyl-2-(4-methyl-1-piperidinyl)-N-(4-{[2-(2-pyridinyl)propanoyl]amino}phenyl)nicotinamide(Example 415)

[0346]N-(4-{[2-(6-amino-2-pyridinyl)ethyl]amino}phenyl)-4-chloro-2-(dimethylamino)benzamide(Example 435)

[0347]2-(dimethylamino)-4-ethyl-N-(4-{[2-(1H-pyrazol-1-yl)ethyl]amino}phenyl)benzamide(Example 473)

[0348] Test 1: Measurement of Inhibition of Apo B Secretion

[0349] HepG2 cells were seeded in Eagles medium containing 10% fetalcalf serum (FCS) at a density of 30000 cells/well in 96-well plates andallowed to grow for 3 days before treatment. At this time, the mediumwas replaced with fresh medium containing 0.1% dimethyl sulfoxide (DMSO)and the indicated concentrations of a test compound. After 15-hourincubation, the amount of Apo B and Apo AI accumulated in the media wasdetermined by ELISA.

[0350] The assay was carried out at ambient temperature. A flat bottomedmicro ELISA plate (manufactured by Nunc) was coated with an anti Apo Bmonoclonal antibody solution (5 mg/ml in 0.05% carbonate buffer, pH 9.6)by adding the antibody solution at a volume of 100 μl per well. After1-hour incubation on a plate mixer, the unbound materials were removedby washing the well 3 times with a washing buffer (phosphate bufferedsaline, pH 7.2 containing 0.1% bovine serum albumin and 0.05% Tween-20).Then 20 μl of a solution of the test compound (dissolved in the culturemedium) and 100 μl of a solution of peroxidase coupled anti Apo Bantibody were added. After 1-hour incubation on a plate mixer, washingwas performed 3 times to remove the unbound materials. A freshlyprepared substrate solution (2.5 mg/ml ortho-phenylene diamine and0.018% H₂O₂ in 0.11 M Na₂HPO₄-0.044 M sodium citrate buffer, pH 5.4) ata volume of 200 μl was then added to each well. After 20-minuteincubation, the enzyme reaction was terminated by adding 50 μl of 0.5 Msulfuric acid. Absorbance of each well was determined at 490 nm using amicroplate reader. Apo B concentration was calculated from a standardcurve generated from purified Apo B standard that was run in parallel inthe same plate. Inhibition of Apo B secretion by the test compound wascalculated taking 0.1% DMSO treated cells as controls.

[0351] Measurement of Apo AI was performed similar to that of Apo B,except for diluting the sample 11-fold with a dilution buffer (phosphatebuffered saline, pH 7.2 containing 0.5% bovine serum albumin and 0.05%Tween-20).

[0352] Apo B secretion inhibitors are identified as compounds thatdecrease Apo B secretion without affecting the secretion of Apo AI.

[0353] Test Results: TABLE 1 Inhibition of Apo B Test compound secretionat 10⁻⁸ M (Example No.) (%) 42 85.8 54 86.3 183 81.2 193 71.5 415 76.2435 85.9 473 75.7

[0354] Test 2: Lipid Lowering Effect on ddY-Mice

[0355] Male ddY-mice were housed in temperature- and humidity-controlledrooms and fed with laboratory chow. The animals were randomizedaccording to their body weight and food was deprived about 16 hoursbefore experiment. Baseline blood sample was collected from the retroorbital venous plexus then the animals were orally dosed with drugs inolive oil (10 ml/kg). For control group, 10 ml/kg of olive oil wasloaded orally. Blood samples were drawn at 2 hours after drugadministration for the measurement of triglyceride (TG) elevation.Plasma TG was determined by conventional enzyme method (The triglycerideE-test Wako).

[0356] Lipid lowering effects were shown in percent of the TG increasein drug treated group, relative to the TG increase in control group.

Lipid lowering effect(%)=(TG increase in drug treated group/TG increasein control group)×100 TABLE 2 Test compound Dose Lipid lowering (ExampleNo.) (mg/kg) effect (%) 42 0.32 33 54 0.32 28 183 0.32 27 435 0.32 52

[0357] For therapeutic administration, the object compound (I) of thepresent invention and pharmaceutically acceptable salts thereof are usedin the form of a conventional pharmaceutical preparation in admixturewith a conventional pharmaceutically acceptable carrier such as anorganic or inorganic solid or liquid excipient which is suitable fororal, parenteral or external administration. The pharmaceuticalpreparation may be compounded in a solid form such as granule, capsule,tablet, dragee, suppository or ointment, or in a liquid form such assolution, suspension or emulsion for injection, intravenous drip,ingestion, eye drop, endermism, inhalation, etc. If needed, there may beincluded in the above preparation auxiliary substance such asstabilizing agent, wetting or emulsifying agent, buffer or any othercommonly used additives.

[0358] The effective ingredient may usually be administered in a unitdose of 0.01 mg/kg to 100 mg/kg, preferably 0.1 mg/kg to 10 mg/kg, 1 to4 times a day. However, the above dosage may be increased or decreasedaccording to age, body weight and conditions of the patient oradministering method.

[0359] Suitable mammal to which the object compounds (I) andpharmaceutical acceptable salts thereof or above preparations areapplied, includes a human being, a companion animal such as a dog and acat, livestock such as a cow and a pig, and the like.

[0360] The object compounds (I) and pharmaceutical acceptable saltsthereof may, if desired, be administered with one or more therapeuticagents and formulated for administration by any convenient route in aconventional manner. Appropriate doses will be readily appreciated bythose skilled in the art. For example, the object compounds (I) andpharmaceutical acceptable salts thereof may be administered incombination with an HMG CoA reductase inhibitor. The object compounds(I) and pharmaceutical acceptable salts thereof may be also administeredin combination with a known anti-obesity agent, for example,β₃-adrenergic receptor agonist, a cholecystokinin-A agonist, a monoaminereuptake inhibitor, a sympathomimetic agent, a serotoninergic agent, adopamine agonist, a melanocyte-stimulating hormone receptor agonist ormimetic, a melanocyte-stimulating hormone receptor analog, a cannabinoidreceptor antagonist, a melanin concentrating hormone antagonist, leptin,a leptin analog, a leptin receptor agonist, a galanin antagonist, alipase inhibitor, a bombesin agonist, a Neuropeptide-Y antagonist, athyromimetic agent, dehydroepiandrosterone or an analog thereof, aglucocorticoid receptor agonist or antagonist, an orexin receptorantagonist, a urocortin binding protein antagonist, a glucagon-likepeptide-1 receptor agonist, a ciliary neurotrophic factor, a humanagouti-related protein antagonist, and the like, for the prophylaxis ortreatment of obesity.

[0361] The following Preparations and Examples are given for the purposeof illustrating the present invention in detail.

[0362] Preparation 1

[0363] To a suspension of 5-nitroindoline (3.28 g), 2-pyridylacetic acidhydrochloride (3.82 g), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimidehydrochloride (4.22 g) and 1-hydroxybenzotriazole hydrate (3.37 g) indichloromethane (100 ml) was added dropwise triethylamine (4.45 g) atambient temperature and the resultant solution was stirred at ambienttemperature for 18 hours. The mixture was poured into water and theseparated organic layer was washed with water and brine, dried overmagnesium sulfate and evaporated in vacuo. The residue was purified bycolumn chromatography on silica gel eluting with ethyl acetate to give5-nitro-1-(2-pyridinylacetyl)indoline (3.58 g) as a yellow solid.

[0364]¹H-NMR(DMSO-d₆): δ 3.26(2H, t, J=8.5 Hz), 4.10(2H, s), 4.33(2H, t,J=8.5 Hz), 7.25-7.35(1H, m), 7.38(1H, d, J=7.8 Hz), 7.75-7.9(1H, m),8.1-8.2(3H, m), 8.50-8.55(1H, m) APCI-MS(m/z): 284(M+H)⁺

[0365] Preparation 2

[0366] To a solution of 5-nitro-1-(2-pyridinylacetyl)indoline (3.54 g)in methanol (50 ml) and tetrahydrofuran (50 ml) was added 10% palladiumon carbon (50% wet, 3.5 g) and the mixture was hydrogenated underhydrogen at atmospheric pressure for 5 hours. After removing thepalladium on carbon by filtration, the filtrate was evaporated in vacuo.The residue was purified by column chromatography on silica gel elutingwith ethyl acetate: methanol (10:1 v/v) to give1-(2-pyridinylacetyl)-5-indolinamine (2.16 g) as pale brown crystals.

[0367]¹H-NMR(DMSO-d₆): δ 3.01(2H, t, J=8.4 Hz), 3.92(2H, s), 4.11(2H, t,J=8.4 Hz), 4.84(2H, br s), 6.32(1H, d, J=8.4 Hz), 6.45(1H, s),7.1-7.2(1H, m), 7.33(1H, d, J=7.8 Hz), 7.7-7.85(2H, m), 8.48(1H, d,J=4.0 Hz) APCI-MS(m/z): 254(M+H)⁺

EXAMPLE 1

[0368] 1-[3-(Dimethylamino)propyl]-3-ethylcarbodiimide (0.19 g) wasadded to a solution of 1-(2-pyridinylacetyl)-5-indolinamine (0.25 g),2-(1-pyrrolidinyl)benzoic acid (0.23 g), 1-hydroxybenzotriazole hydrate(0.16 g) and 4-dimethylaminopyridine (6 mg) in N,N-dimethylformamide (5ml) under ice-cooling and the mixture was stirred at ambient temperaturefor 18 hours. The reaction mixture was poured into a mixture of ethylacetate and water. The separated organic layer was washed with water,dried over magnesium sulfate and evaporated in vacuo. The residue wastriturated with ethyl acetate to giveN-[1-(2-pyridinylacetyl)-2,3-dihydro-1H-indol-5-yl]-2-(1-pyrrolidinyl)benzamide(0.27 g).

[0369]¹H-NMR(DMSO-d₆): δ 1.75-1.95(4H, m), 3.08-3.29(4H, m), 3.16(2H, t,J=8.4 Hz), 4.00(2H, s), 4.21(2H, t, J=8.4 Hz), 6.65-6.82(2H, m),7.21-7.47(5H, m), 7.69(1H, s), 7.76(1H, dt, J=1.8 Hz, 7.6 Hz), 7.96(1H,d, J=8.7 Hz), 8.50(1H, dd, J=0.9 Hz, 4.2 Hz), 10.27(1H, s) (−)ESI-MS:425(M−H)⁻

EXAMPLE 22-(1-Piperidinyl)-N-[1-(2-pyridinylacetyl)-2,3-dihydro-1H-indol-5-yl]benzamide

[0370] The title compound was obtained in a similar manner as in Example1 from 1-(2-pyridinylacetyl)-5-indolinamine and 2-(1-piperidinyl)benzoicacid.

[0371]¹H-NMR(DMSO-d₆): δ 1.45-1.76(6H, m), 2.87-3.01(4H, m), 3.19(2H, t,J=8.4 Hz), 4.01(2H, s), 4.23(2H, t, J=8.4 Hz), 7.16-7.57(6H, m),7.72-7.90(3H, m), 8.02(1H, d, J=8.6 Hz), 8.48-8.55(1H, m), 11.68(1H, s)(+)APCI-MS: 441(M+H)⁺

EXAMPLE 32-(3,6-Dihydro-1(2H)-pyridinyl)-N-[1-(2-pyridinylacetyl)-2,3-dihydro-1H-indol-5-yl]benzamide

[0372] The title compound was obtained in a similar manner as in Example1 from 1-(2-pyridinylacetyl)-5-indolinamine and2-(3,6-dihydro-1(2H)-pyridinyl)benzoic acid.

[0373]¹H-NMR(DMSO-d₆): δ 2.21-2.37(2H, m), 3.07-3.27(4H, m),3.42-3.54(2H, m), 4.00(2H, s), 4.22(2H, t, J=8.4 Hz), 5.77-5.97(2H, m),7.18-7.44(5H, m), 7.46-7.60(1H, m), 7.67-7.82(2H, m), 7.89(1H, dd, J=1.4Hz, 7.6 Hz), 7.98(1H, d, J=8.6 Hz), 8.47-8.55(1H, m), 11.95(1H, s)(+)ESI-MS: 439(M+H)⁺, 461(M+Na)⁺

EXAMPLE 42-(4-Methyl-1-piperidinyl)-N-[1-(2-pyridinylacetyl)-2,3-dihydro-1H-indol-5-yl]benzamide

[0374] The title compound was obtained in a similar manner as in Example1 from 1-(2-pyridinylacetyl)-5-indolinamine and2-(4-methyl-1-piperidinyl)benzoic acid.

[0375]¹H-NMR(DMSO-d₆): δ 0.93(3H, d, J=6.0 Hz), 1.21-1.62(3H, m),1.62-1.80(2H, m), 2.67-2.88(2H, m), 3.05-3.27(4H, m), 4.01(2H, s),4.23(2H, t, J=8.4 Hz), 7.15-7.57(6H, m), 7.70-7.90(3H, m), 8.02(1H, d,J=8.6 Hz), 8.47-8.57(1H, m), 11.63(1H, s) (+)ESI-MS: 455(M+H)⁺,477(M+Na)⁺

[0376] Preparation 3

[0377] A mixture of methyl4-methyl-2-(trifluoromethanesulfonyloxy)benzoate (5.0 g) and pyrrolidine(4.2 ml) in acetonitrile (15.0 ml) was stirred under reflux for 20hours. The solvent was removed by concentration. The residue waspurified by column chromatography on silica gel using a mixture ofhexane and ethyl acetate (9:1 v/v) as an eluant. The eluted fractionscontaining the desired product were collected and evaporated in vacuo togive methyl 4-methyl-2-(1-pyrrolidinyl)benzoate (2.07 g).

[0378]¹H-NMR(DMSO-d₆): δ 1.83-1.90(4H, m), 2.26(3H, s), 3.09-3.16(4H,m), 3.76(3H, s), 6.50(1H, dd, J=0.8 Hz, 7.9 Hz), 6.61(1H, d, J=0.8 Hz),7.33(1H, d, J=7.9 Hz) (+)APCI-MS: 220(M+H)⁺

[0379] Preparation 4

[0380] A mixture of methyl 4-methyl-2-(1-pyrrolidinyl)benzoate (2.0 g)and sodium hydroxide (1.1 g) in a mixture of methanol (30 ml) and water(7.3 ml) was stirred under reflux for 24 hours. The solvent was removedby concentration. To the residue was added a mixture of ethyl acetate,tetrahydrofuran and water and the mixture was adjusted to pH 5.5 with6N-hydrochloric acid. The separated organic layer was dried overmagnesium sulfate and evaporated in vacuo. The residue was trituratedwith diisopropyl ether to give 4-methyl-2-(1-pyrrolidinyl)benzoic acid(1.48 g).

[0381]¹H-NMR(DMSO-d₆): δ 1.81-1.99(4H, m), 2.29(3H, s), 3.08-3.26(4H,m), 6.66(1H, d, J=7.8 Hz), 6.82(1H, s), 7.50(1H, d, J=7.8 Hz), 13.66(1H,s) (−)ESI-MS: 204 (M−H)⁻

EXAMPLE 54-Methyl-N-[1-(2-pyridinylacetyl)-2,3-dihydro-1H-indol-5-yl]-2-(1-pyrrolidinyl)benzamide

[0382] The title compound was obtained in a similar manner as in Example1 from 1-(2-pyridinylacetyl)-5-indolinamine and4-methyl-2-(1-pyrrolidinyl)benzoic acid.

[0383]¹H-NMR(DMSO-d₆): δ 1.72-1.94(4H, m), 2.28(3H, s), 3.06-3.29(6H,m), 4.00(2H, s), 4.21(2H, t, J=8.3 Hz), 6.55(1H, d, J=7.7 Hz), 6.60(1H,s), 7.19(1H, d, J=7.7 Hz), 7.23-7.46(3H, m), 7.69(1H, s), 7.71-7.82(1H,m), 7.96(1H, d, J=8.7 Hz), 8.46-8.55(1H, m), 10.23(1H, s) (−)ESI-MS:439(M−H)⁻

[0384] Preparation 5

Benzyl 4-methyl-2-(1-piperidinyl)benzoate

[0385] The title compound was obtained in a similar manner as inPreparation 3 from benzyl4-methyl-2-(trifluoromethanesulfonyloxy)benzoate and piperidine.

[0386]¹H-NMR(DMSO-d₆): δ 1.38-1.60(6H, m), 2.29(3H, s), 2.82-2.93(4H,m), 5.28(2H, s), 6.78(1H, d, J=8.0 Hz), 6.87(1H, s), 7.29-7.55(6H, m)

[0387] Preparation 6

[0388] To a mixture of benzyl 4-methyl-2-(1-piperidinyl)benzoate (5.6 g)in methanol (60 ml) was added 10% palladium on carbon (2.0 g, 50% wet).The reaction mixture was stirred at ambient temperature for 5 hoursunder hydrogen atmosphere. The catalyst was filtered off and the solventwas removed by concentration. The residue was triturated with a mixtureof hexane and diisopropyl ether to give4-methyl-2-(1-piperidinyl)benzoic acid (3.52 g).

[0389]¹H-NMR(DMSO-d₆): δ 1.54-1.83(6H, m), 2.38(3H, s), 2.96-3.10(4H,m), 7.25(1H, d, J=8.0 Hz), 7.56(1H, s), 7.92(1H, d, J=8.0 Hz), 18.13(1H,s) (−)ESI-MS: 218(M−H)⁻

EXAMPLE 64-Methyl-2-(1-piperidinyl)-N-[1-(2-pyridinylacetyl)-2,3-dihydro-1H-indol-5-yl]benzamide

[0390] The title compound was obtained in a similar manner as in Example1 from 1-(2-pyridinylacetyl)-5-indolinamine and4-methyl-2-(1-piperidinyl)benzoic acid.

[0391]¹H-NMR(DMSO-d₆): δ 1.45-1.77(6H, m), 2.35(3H, s), 2.86-3.00(4H,m), 3.18(2H, t, J=8.4 Hz), 4.01(2H, s), 4.23(2H, t, J=8.4 Hz), 7.05(1H,d, J=8.0 Hz), 7.17(1H, s), 7.23-7.32(1H, m), 7.32-7.46(2H, m),7.71-7.87(3H, m), 8.02(1H, d, J=8.7 Hz), 8.47-8.54(1H, m), 11.90(1H, s)(+)APCI-MS: 455(M+H)⁺

[0392] Preparation 7

Benzyl 4-methyl-2-(4-methyl-1-piperidinyl)benzoate

[0393] The title compound was obtained in a similar manner as inPreparation 3 from benzyl4-methyl-2-(trifluoromethanesulfonyloxy)benzoate and 4-methylpiperidine.

[0394]¹H-NMR(DMSO-d₆): δ 0.87(3H, d, J=6.2 Hz), 1.04-1.27(2H, m),1.27-1.48(1H, m), 1.48-1.62(2H, m), 2.29(3H, s), 2.54-2.71(2H, m),3.08-3.22(2H, m), 5.27(2H, s), 6.78(1H, d, J=8.0 Hz), 6.87(1H, s),7.30-7.56(6H, m)

[0395] Preparation 8

4-Methyl-2-(4-methyl-1-piperidinyl)benzoic acid

[0396] The title compound was obtained in a similar manner as inPreparation 6 from benzyl 4-methyl-2-(4-methyl-1-piperidinyl)benzoate.

[0397]¹H-NMR(DMSO-d₆): δ 1.00(3H, d, J=6.4 Hz), 1.20-1.45(2H, m),1.54-1.77(1H, m), 1.77-1.73(2H, m), 2.38(3H, s), 2.94-3.17(4H, m),7.24(1H, d, J=8.0 Hz), 7.57(1H, s), 7.92(1H, d, J=8.0 Hz) (+)ESI-MS:234(M+H)⁺

EXAMPLE 74-Methyl-2-(4-methyl-1-piperidinyl)-N-[1-(2-pyridinylacetyl)-2,3-dihydro-1H-indol-5-yl]benzamide

[0398] The title compound was obtained in a similar manner as in Example1 from 1-(2-pyridinylacetyl)-5-indolinamine and4-methyl-2-(4-methyl-1-piperidinyl)benzoic acid.

[0399]¹H-NMR(DMSO-d₆): δ 0.95(3H, d, J=6.0 Hz), 1.18-1.65(3H, m),1.65-1.80(2H, m), 2.34(3H, s), 2.69-2.86(2H, m), 3.04-3.25(4H, m),4.01(2H, s), 4.23(2H, t, J=8.4 Hz), 7.04(1H, d, J=8.0 Hz), 7.16(1H, s),7.24-7.33(1H, m), 7.33-7.43(2H, m), 7.71-7.84(3H, m), 8.02(1H, d, J=8.6Hz), 8.47-8.54(1H, m), 11.85(1H, s) (+)ESI-MS: 469(M+H)⁺, 491(M+Na)⁺

[0400] Preparation 9

Benzyl 2-(4,4-dimethyl-1-piperidinyl)-4-methylbenzoate

[0401] The title compound was obtained in a similar manner as inPreparation 3 from benzyl4-methyl-2-(trifluoromethanesulfonyloxy)benzoate and4,4-dimethylpiperidine.

[0402]¹H-NMR(DMSO-d₆): δ 0.89(6H, s), 1.32(4H, t, J=5.5 Hz), 2.29(3H,s), 2.88(4H, t, J=5.5 Hz), 5.27(2H, s), 6.78(1H, d, J=7.9 Hz), 6.91(1H,s), 7.30-7.54(6H, m)

[0403] Preparation 10

2-(4,4-Dimethyl-1-piperidinyl)-4-methylbenzoic acid

[0404] The title compound was obtained in a similar manner as inPreparation 6 from benzyl2-(4,4-dimethyl-1-piperidinyl)-4-methylbenzoate.

[0405]¹H-NMR(DMSO-d₆): δ 1.07(6H, s), 7.56(4H, t, J=5.6 Hz), 2.39(3H,s), 3.03(4H, t, J=5.6 Hz), 7.24(1H, d, J=7.9 Hz), 7.71(1H, s), 7.92(1H,d, J=7.9 Hz) (−)ESI-MS: 246(M−H)⁻

EXAMPLE 82-(4,4-Dimethyl-1-piperidinyl)-4-methyl-N-[1-(2-pyridinylacetyl)-2,3-dihydro-1H-indol-5-yl]benzamide

[0406] The title compound was obtained in a similar manner as in Example1 from 1-(2-pyridinylacetyl)-5-indolinamine and2-(4,4-dimethyl-1-piperidinyl)-4-methylbenzoic acid.

[0407]¹H-NMR(DMSO-d₆): δ 0.98(6H, s), 1.45-1.59(4H, m), 2.35(3H, s),2.87-3.00(4H, m), 3.17(2H, t, J=8.4 Hz), 4.01(2H, s), 4.23(2H, t, J=8.4Hz), 7.04(1H, d, J=8.0 Hz), 7.21-7.33(2H, m), 7.33-7.45(2H, m),7.71-7.85(3H, m), 8.02(1H, d, J=8.6 Hz), 8.48-8.54(1H, m), 11.92(1H, s)(+)ESI-MS: 483(M+H)⁺, 505(M+Na)⁺

[0408] Preparation 11

Benzyl 4-methyl-2-(4-morpholinyl)benzoate

[0409] The title compound was obtained in a similar manner as inPreparation 3 from benzyl4-methyl-2-(trifluoromethanesulfonyloxy)benzoate and morpholine.

[0410]¹H-NMR(DMSO-d₆): δ 2.31(3H, s), 2.83-2.96(4H, m), 3.52-3.64(4H,m), 5.28(2H, s), 6.85(1H, d, J=8.0 Hz), 6.90(1H, s), 7.30-7.50(5H, m),7.58(1H, d, J=8.0 Hz)

[0411] Preparation 12

4-Methyl-2-(4-morpholinyl)benzoic acid

[0412] The title compound was obtained in a similar manner as inPreparation 6 from benzyl 4-methyl-2-(4-morpholinyl)benzoate.

[0413]¹H-NMR(DMSO-d₆): δ 2.38(3H, s), 2.98-3.10(4H, m), 3.73-3.86(4H,m), 7.20(1H, d, J=8.0 Hz), 7.50(1H, s), 7.88(1H, d, J=8.0 Hz), 16.41(1H,s) (−)ESI-MS: 220(M−H)⁻

EXAMPLE 94-Methyl-2-(4-morpholinyl)-N-[1-(2-pyridinylacetyl)-2,3-dihydro-1H-indol-5-yl]benzamide

[0414] The title compound was obtained in a similar manner as in Example1 from 1-(2-pyridinylacetyl)-5-indolinamine and4-methyl-2-(4-morpholinyl)benzoic acid.

[0415]¹H-NMR(DMSO-d₆): δ 2.35(3H, s), 2.89-3.04(4H, m), 3.18(2H, t,J=8.3 Hz), 3.65-3.80(4H, m), 4.01(2H, s), 4.22(2H, t, J=8.3 Hz),7.03(1H, d, J=8.1 Hz), 7.12(1H, s), 7.23-7.33(1H, m), 7.37(1H, d, J=7.7Hz), 7.43-7.53(1H, m), 7.65-7.84(3H, m), 8.02(1H, d, J=8.7 Hz),8.47-8.54(1H, m), 11.20(1H, s) (+)APCI-MS: 457(M+H)⁺

[0416] Preparation 13

Benzyl 4-methyl-2-(4-methyl-1-piperazinyl)benzoate

[0417] The title compound was obtained in a similar manner as inPreparation 3 from benzyl4-methyl-2-(trifluoromethanesulfonyloxy)benzoate and 1-methylpiperazine.

[0418]¹H-NMR(DMSO-d₆): δ 2.15(3H, s), 2.25-2.39(4H, m), 2.30(3H, s),2.86-2.97(4H, m), 5.27(2H, s), 6.81(1H, d, J=8.0 Hz), 6.88(1H, s),7.31-7.50(5H, m), 7.53(1H, d, J=8.0 Hz)

[0419] Preparation 14

4-Methyl-2-(4-methyl-1-piperazinyl)benzoic acid

[0420] The title compound was obtained in a similar manner as inPreparation 6 from benzyl 4-methyl-2-(4-methyl-1-piperazinyl)benzoate.

[0421]¹H-NMR(DMSO-d₆): δ 2.37(3H, s), 2.46(3H, s), 2.70-2.94(4H, m),3.06-3.22(4H, m), 7.16(1H, d, J=7.9 Hz), 7.39(1H, s), 7.86(1H, d, J=7.9Hz), 14.51-17.40(1H, br) (−)ESI-MS: 233(M−H)⁻

EXAMPLE 104-Methyl-2-(4-methyl-1-piperazinyl)-N-[1-(2-pyridinylacetyl)-2,3-dihydro-1H-indol-5-yl]benzamide

[0422] The title compound was obtained in a similar manner as in Example1 from 1-(2-pyridinylacetyl)-5-indolinamine and4-methyl-2-(4-methyl-1-piperazinyl)benzoic acid.

[0423]¹H-NMR(DMSO-d₆): δ 2.20(3H, s), 2.35(3H, s), 2.40-2.57(4H, m),2.90-3.04(4H, m), 3.18(2H, t, J=8.3 Hz), 4.01(2H, s), 4.23(2H, t, J=8.3Hz), 7.03(1H, d, J=8.0 Hz), 7.14(1H, s), 7.28(1H, dd, J=5.1 Hz, 6.8 Hz),7.33-7.48(2H, m), 7.70-7.85(3H, m), 8.02(1H, d, J=8.7 Hz), 8.47-8.55(1H,m), 11.44(1H, s) (+)APCI-MS: 470(M+H)⁺

[0424] Preparation 15

Benzyl 4-methyl-2-(4-thiomorpholinyl)benzoate

[0425] The title compound was obtained in a similar manner as inPreparation 3 from benzyl4-methyl-2-(trifluoromethanesulfonyloxy)benzoate and thiomorpholine.

[0426]¹H-NMR(DMSO-d₆): δ 2.31(3H, s), 2.55-2.67(4H, m), 3.11-3.22(4H,m), 5.29(2H, s), 6.87(1H, d, J=8.0 Hz), 6.95(1H, s), 7.31-7.52(5H, m),7.56(1H, d, J=8.0 Hz)

[0427] Preparation 16

4-Methyl-2-(4-thiomorpholinyl)benzoic acid

[0428] The title compound was obtained in a similar manner as inPreparation 6 from benzyl 4-methyl-2-(4-thiomorpholinyl)benzoate.

[0429]¹H-NMR(DMSO-d₆): δ 2.38(3H, s), 2.79-2.92(4H, m), 3.18-3.32(4H,m), 7.21(1H, d, J=8.0 Hz), 7.50(1H, s), 7.89(1H, d, J=8.0 Hz), 16.43(1H,s) (−)ESI-MS: 236(M−H)⁻

EXAMPLE 114-Methyl-N-[1-(2-pyridinylacetyl)-2,3-dihydro-1H-indol-5-yl]-2-(4-thiomorpholinyl)benzamide

[0430] The title compound was obtained in a similar manner as in Example1 from 1-(2-pyridinylacetyl)-5-indolinamine and4-methyl-2-(4-thiomorpholinyl)benzoic acid.

[0431]¹H-NMR(DMSO-d₆): δ 2.35(3H, s), 2.68-2.83(4H, m), 3.10-3.30(6H,m), 4.01(2H, s), 4.23(2H, t, J=8.4 Hz), 7.03(1H, d, J=7.9 Hz), 7.12(1H,s), 7.23-7.50(3H, m), 7.68(1H, d, J=7.9 Hz), 7.71-7.84(2H, m), 8.02(1H,d, J=8.6 Hz), 8.47-8.55(1H, m), 11.14(1H, s) (+)ESI-MS: 473(M+H)⁺,495(M+Na)⁺

[0432] Preparation 17

[0433] OXONE® (potassium peroxymonosulfate) (2.9 g) was added to amixture of 4-methyl-2-(4-thiomorpholinyl)benzoic acid (0.5 g) andtetra-n-butylammonium hydrogensulfate (0.14 g) in a mixture of ethylacetate (7.5 ml) and water (17.5 ml) and the mixture was stirred at 30°C. for 5 hours. The mixture was extracted with ethyl acetate. Theextract layer was washed with water, dried over magnesium sulfate andevaporated in vacuo. The residue was triturated with diisopropyl etherto give 2-(1,1-dioxido-4-thiomorpholinyl)-4-methylbenzoic acid (0.18 g).

[0434]¹H-NMR(DMSO-d₆): δ 2.33(3H, s), 3.21-3.37(4H, m), 3.37-3.53(4H,m), 6.99(1H, d, J=7.9 Hz), 7.18(1H, s), 7.71(1H, d, J=7.9 Hz), 13.33(1H,s) (−)ESI-MS: 268(M−H)⁻

EXAMPLE 122-(1,1-Dioxido-4-thiomorpholinyl)-4-methyl-N-[1-(2-pyridinylacetyl)-2,3-dihydro-1H-indol-5-yl]benzamide

[0435] The title compound was obtained in a similar manner as in Example1 from 1-(2-pyridinylacetyl)-5-indolinamine and2-(1,1-dioxido-4-thiomorpholinyl)-4-methylbenzoic acid.

[0436]¹H-NMR(DMSO-d₆): δ 2.34(3H, s), 3.08-3.26(6H, m), 3.36-3.50(4H,m), 4.01(2H, s), 4.23(2H, t, J=8.4 Hz), 6.99(1H, d, J=7.9 Hz), 7.09(1H,s), 7.23-7.33(1H, m), 7.33-7.52(3H, m), 7.70-7.85(2H, m), 8.01(1H, d,J=8.7 Hz), 8.46-8.56(1H, m), 10.36(1H, s) (+)ESI-MS: 505(M+H)⁺,527(M+Na)⁺

[0437] Preparation 18

Benzyl 2-(hexahydro-1H-azepin-1-yl)-4-methylbenzoate

[0438] The title compound was obtained in a similar manner as inPreparation 3 from benzyl4-methyl-2-(trifluoromethanesulfonyloxy)benzoate and hexamethyleneimine.

[0439] 1H-NMR(DMSO-d₆): δ 1.41-1.55(4H, m), 1.55-1.74(4H, m), 2.26(3H,s), 3.12-3.27(4H, m), 5.26(2H, s), 6.55(1H, d, J=7.5 Hz), 6.77(1H, s),7.30-7.50(6H, m)

[0440] Preparation 19

2-(Hexahydro-1H-azepin-1-yl)-4-methylbenzoic acid

[0441] The title compound was obtained in a similar manner as inPreparation 6 from benzyl 2-(hexahydro-1H-azepin-1-yl)-4-methylbenzoate.

[0442]¹H-NMR(DMSO-d₆): δ 1.61-1.91(8H, m), 2.37(3H, s), 3.13-3.27(4H,m), 7.20(1H, d, J=8.0 Hz), 7.48(1H, s), 7.87(1H, d, J=8.0 Hz), 18.19(1H,s) (−)ESI-MS: 232(M−H)⁻

EXAMPLE 13

[0443]2-(Hexahydro-1H-azepin-1-yl)-4-methyl-N-[1-(2-pyridinylacetyl)-2,3-dihydro-1H-indol-5-yl]benzamide

[0444] The title compound was obtained in a similar manner as in Example1 from 1-(2-pyridinylacetyl)-5-indolinamine and2-(hexahydro-1H-azepin-1-yl)-4-methylbenzoic acid.

[0445]¹H-NMR(DMSO-d₆): δ 1.52-1.65(4H, m), 1.65-1.84(4H, m), 2.31(3H,s), 3.08-3.29(6H, m), 4.01(2H, s), 4.22(2H, t, J=8.3 Hz), 6.84(1H, d,J=7.6 Hz), 7.01(1H, s), 7.24-7.43(3H, m), 7.51(1H, d, J=7.8 Hz),7.70-7.83(2H, m), 7.99(1H, d, J=8.7 Hz), 8.47-8.54(1H, m), 11.23(1H, s)(+)ESI-MS: 469(M+H)⁺, 491(M+Na)⁺

[0446] Preparation 20

[0447] A mixture of 2-fluoro-4-(trifluoromethyl)benzonitrile (5.0 g) andpiperidine (7.8 ml) in acetonitrile (25.0 ml) was stirred under refluxfor 18 hours. The solvent was removed by concentration. To the residuewas added a mixture of ethyl acetate and water, and the mixture wasadjusted to pH 2 with 6N-hydorochloric acid. The separated organic layerwas washed with water, dried over magnesium sulfate and evaporated invacuo to give 2-(1-piperidinyl)-4-(trifluoromethyl)-benzonitrile (6.7g).

[0448]¹H-NMR(DMSO-d₆): δ 2.50-2.77(6H, m), 3.16-3.27(4H, m),7.30-7.41(2H, m), 7.92(1H, d, J=8.5 Hz)

[0449] Preparation 21

[0450] A mixture of 2-(1-piperidinyl)-4-(trifluoromethyl)benzonitrile(6.7 g) and sodium hydroxide (2.1 g) in ethylene glycol (27 ml) wasstirred at 180° C. for 6 hours. After the mixture was added to water (27ml) at 80° C., the mixture was stirred at 80° C. for 1 hour. Thereaction mixture was poured into a mixture of ethyl acetate and water,and the mixture was adjusted to pH 3 with 6N-hydrochloric acid. Theseparated organic layer was washed with water, dried over magnesiumsulfate and evaporated in vacuo. The residue was triturated withdiisopropyl ether to give 2-(1-piperidinyl)-4-(trifluoromethyl)benzoicacid (6.5 g).

[0451] 1H-NMR(DMSO-d₆): δ 1.54-1.83(6H, m), 3.06-3.21(4H, m), 7.68(1H,d, J=8.1 Hz), 7.99(1H, s), 8.12(1H, d, J=8.1 Hz), 17.19(1H, s)(−)ESI-MS: 272(M−H)⁻

EXAMPLE 142-(1-Piperidinyl)-N-[1-(2-pyridinylacetyl)-2,3-dihydro-1H-indol-5-yl]-4-(trifluoromethyl)benzamide

[0452] The title compound was obtained in a similar manner as in Example1 from 1-(2-pyridinylacetyl)-5-indolinamine and2-(1-piperidinyl)-4-(trifluoromethyl)benzoic acid.

[0453]¹H-NMR(DMSO-d₆): δ 1.40-1.70(6H, m), 2.94-3.07(4H, m), 3.18(2H, t,J=8.4 Hz), 4.01(2H, s), 4.23(2H, t, J=8.4 Hz), 7.28(1H, dd, J=5.0 Hz,6.7 Hz), 7.34-7.52(4H, m), 7.71-7.87(3H, m), 8.02(1H, d, J=8.6 Hz),8.47-8.54(1H, m), 10.93(1H, s) (−)ESI-MS: 507(M−H)⁻

[0454] Preparation 22

4-Chloro-2-(1-piperidinyl)benzonitrile

[0455] The title compound was obtained in a similar manner as inPreparation 20 from 4-chloro-2-fluorobenzonitrile and piperidine.

[0456]¹H-NMR(DMSO-d₆): δ 1.48-1.75(6H, m), 3.08-3.21(4H, m), 7.09(1H,dd, J=1.9 Hz, 8.2 Hz), 7.15(1H, d, J=1.9 Hz), 7.70(1H, d, J=8.2 Hz)

[0457] Preparation 23

4-Chloro-2-(1-piperidinyl)benzoic acid

[0458] The title compound was obtained in a similar manner as inPreparation 21 from 4-chloro-2-(1-piperidinyl)benzonitrile.

[0459]¹H-NMR(DMSO-d₆): δ 1.51-1.82(6H, m), 2.98-3.17(4H, m), 7.44(1H,dd, J=2.0 Hz, 8.3 Hz), 7.80(1H, d, J=2.0 Hz), 7.97(1H, d, J=8.3 Hz),17.23(1H, s) (−)ESI-MS: 238(M−H)⁻

EXAMPLE 154-Chloro-2-(1-piperidinyl)-N-[1-(2-pyridinylacetyl)-2,3-dihydro-1H-indol-5-yl]benzamide

[0460] The title compound was obtained in a similar manner as in Example1 from 1-(2-pyridinylacetyl)-5-indolinamine and4-chloro-2-(1-piperidinyl)benzoic acid.

[0461]¹H-NMR(DMSO-d₆): δ 1.04-1.75(6H, m), 2.86-3.03(4H, m), 3.18(2H, t,J=8.4 Hz), 4.01(2H, s), 4.23(2H, t, J=8.4 Hz), 7.17-7.46(5H, m),7.69-7.84(3H, m), 8.01(1H, d, J=8.6 Hz), 8.46-8.54(1H, m), 11.16(1H, s)(−)ESI-MS: 473(M−H)⁻

[0462] Preparation 24

4-Methoxy-2-(1-piperidinyl)benzonitrile

[0463] The title compound was obtained in a similar manner as inPreparation 20 from 2-fluoro-4-methoxybenzonitrile and piperidine.

[0464]¹H-NMR(DMSO-d₆): δ 1.47-1.75(6H, m), 3.03-3.16(4H, m), 3.81(3H,s), 6.57(1H, d, J=2.3 Hz), 6.62(1H, dd, J=2.3 Hz, 8.5 Hz), 7.59(1H, d,J=8.5 Hz)

[0465] Preparation 25

4-Methoxy-2-(1-piperidinyl)benzoic acid

[0466] The title compound was obtained in a similar manner as inPreparation 21 from 4-methoxy-2-(1-piperidinyl)benzonitrile.¹H-NMR(DMSO-d₆): δ 1.56-1.81(6H, m), 2.97-3.09(4H, m), 3.85(3H, s),6.99(1H, dd, J=2.5 Hz, 8.7 Hz), 7.25(1H, d, J=2.5Hz), 7.97(1H, d, J=8.7Hz), 17.71(1H, s) (−)ESI-MS: 234(M−H)⁻

EXAMPLE 164-Methoxy-2-(1-piperidinyl)-N-[1-(2-pyridinylacetyl)-2,3-dihydro-1H-indol-5-yl]benzamide

[0467] The title compound was obtained in a similar manner as in Example1 from 1-(2-pyridinylacetyl)-5-indolinamine and4-methoxy-2-(1-piperidinyl)benzoic acid.

[0468]¹H-NMR(DMSO-d₆): δ 1.47-1.80(6H, m), 2.85-3.00(4H, m), 3.18(2H, t,J=8.3 Hz), 3.82(3H, s), 4.01(2H, s), 4.22(2H, t, J=8.3 Hz),6.77-6.88(2H, m), 7.28(1H, dd, J=5.2 Hz, 7.1 Hz), 7.34-7.46(2H, m),7.72-7.85(2H, m), 7.89(1H, d, J=8.3 Hz), 8.02(1H, d, J=8.6 Hz),8.47-8.56(1H, m), 11.82(1H, s) (+)ESI-MS: 471(M+H)⁺, 493(M+Na)⁺

[0469] Preparation 26

Benzyl 5-methyl-2-(1-pyrrolidinyl)benzoate

[0470] The title compound was obtained in a similar manner as inPreparation 3 from benzyl5-methyl-2-(trifluoromethanesulfonyloxy)benzoate and pyrrolidine.

[0471] 1H-NMR(DMSO-d₆): δ 1.73-1.90(4H, m), 2.19(3H, s), 2.99-3.13(4H,m), 5.27(2H, s), 6.71(1H, d, J=8.5 Hz), 7.13(1H, dd, J=2.0 Hz, 8.5 Hz),7.27(1H, d, J=2.0 Hz), 7.33-7.50(5H, m)

[0472] Preparation 27

5-Methyl-2-(1-pyrrolidinyl)benzoic acid

[0473] The title compound was obtained in a similar manner as inPreparation 6 from benzyl 5-methyl-2-(1-pyrrolidinyl)benzoate.

[0474]¹H-NMR(DMSO-d₆): δ 1.86-2.01(4H, m), 2.26(3H, s), 3.10-3.25(4H,m), 7.06(1H, d, J=8.4 Hz), 7.25(1H, dd, J=1.8 Hz, 8.4 Hz), 7.50(1H, d,J=1.8 Hz), 14.75(1H, s) (+)ESI-MS: 206(M+H)⁺, 228(M+Na)⁺

EXAMPLE 175-Methyl-N-[1-(2-pyridinylacetyl)-2,3-dihydro-1H-indol-5-yl]-2-(1-pyrrolidinyl)benzamide

[0475] The title compound was obtained in a similar manner as in Example1 from 1-(2-pyridinylacetyl)-5-indolinamine and5-methyl-2-(1-pyrrolidinyl)benzoic acid.

[0476]¹H-NMR(DMSO-d₆): δ 1.75-1.94(4H, m), 2.23(3H, s), 3.06-3.25(6H,m), 4.00(2H, s), 4.21(2H, t, J=8.4 Hz), 6.71(1H, d, J=8.2 Hz),7.05-7.17(2H, m), 7.23-7.46(3H, m), 7.69(1H, s), 7.74(1H, dt, J=1.8 Hz,7.7Hz), 7.97(1H, d, J=8.7 Hz), 8.47-8.54(1H, m), 10.36(1H, s) (+)ESI-MS:441(M+H)⁺, 463(M+Na)⁺

[0477] Preparation 28

Benzyl 5-methyl-2-(1-piperidinyl)benzoate

[0478] The title compound was obtained in a similar manner as inPreparation 3 from benzyl5-methyl-2-(trifluoromethanesulfonyloxy)benzoate and piperidine.

[0479]¹H-NMR(DMSO-d₆): δ 1.36-1.59(6H, m), 2.24(3H, s), 2.76-2.88(4H,m), 5.29(2H, s), 6.99(1H, d, J=8.3 Hz), 7.19-7.51(7H, m)

[0480] Preparation 29

5-Methyl-2-(1-piperidinyl)benzoic acid

[0481] The title compound was obtained in a similar manner as inPreparation 6 from benzyl 5-methyl-2-(1-piperidinyl)benzoate.

[0482]¹H-NMR(DMSO-d₆): δ 1.52-1.87(6H, m), 2.35(3H, s), 2.90-3.14(4H,m), 7.47(1H, d, J=8.2 Hz), 7.62(1H, d, J=8.2 Hz), 7.85(1H, s), 17.20(1H,s) (+)ESI-MS: 220(M+H)⁺, 242(M+Na)⁺

EXAMPLE 185-Methyl-2-(1-piperidinyl)-N-[1-(2-pyridinylacetyl)-2,3-dihydro-1H-indol-5-yl]benzamide

[0483] The title compound was obtained in a similar manner as in Example1 from 1-(2-pyridinylacetyl)-5-indolinamine and5-methyl-2-(1-piperidinyl)benzoic acid

[0484]¹H-NMR(DMSO-d₆): δ 1.46-1.86(6H, m), 2.31(3H, s), 2.82-2.97(4H,m), 3.18(2H, t, J=8.3 Hz), 4.01(2H, s), 4.23(2H, t, J=8.3 Hz),7.21-7.46(5H, m), 7.71-7.84(3H, m), 8.02(1H, d, J=8.6 Hz), 8.47-8.54(1H,m), 12.06(1H, s) (+)ESI-MS: 455(M+H)⁺, 477(M+Na)⁺

[0485] Preparation 30

2-(1-Piperidinyl)-3-(trifluoromethyl)benzonitrile

[0486] The title compound was obtained in a similar manner as inPreparation 20 from 2-fluoro-3-(trifluoromethyl)benzonitrile andpiperidine.

[0487]¹H-NMR(DMSO-d₆): δ 1.46-1.71(6H, m), 2.98-3.21(4H, m), 7.56(1H, t,J=7.7 Hz), 8.02(1H, dd, J=1.4 Hz, 7.7 Hz), 8.09(1H, dd, J=1.4 Hz, 7.7Hz) (+)ESI-MS: 255(M+H)⁺, 277(M+Na)⁺

[0488] Preparation 31

2-(1-Piperidinyl)-3-(trifluoromethyl)benzoic acid

[0489] The title compound was obtained in a similar manner as inPreparation 21 from 2-(1-piperidinyl)-3-(trifluoromethyl)benzonitrile.

[0490]¹H-NMR(DMSO-d₆): δ 1.35-1.70(6H, m), 2.87-3.13(4H, m), 7.40(1H,dd, J=7.5 Hz, 8.0 Hz), 7.71-7.86(2H, m), 13.45(1H, s)

EXAMPLE 192-(1-Piperidinyl)-N-[1-(2-pyridinylacetyl)-2,3-dihydro-1H-indol-5-yl]-3-(trifluoromethyl)benzamide

[0491] The title compound was obtained in a similar manner as in Example1 from 1-(2-pyridinylacetyl)-5-indolinamine and2-(1-piperidinyl)-3-(trifluoromethyl)benzoic acid.

[0492]¹H-NMR(DMSO-d₆): δ 1.25-1.63(6H, m), 2.89-3.05(4H, m), 3.18(2H, t,J=8.3 Hz), 4.01(2H, s), 4.23(2H, t, J=8.3 Hz), 7.23-7.33(1H, m),7.33-7.49(3H, m), 7.61-7.83(4H, m), 8.00(1H, d, J=8.7 Hz), 8.47-8.53(1H,m), 10.45(1H, s) (−)ESI-MS: 507(M−H)⁻

[0493] Preparation 32

[0494] To a solution of 6-methyl-2-pyridinamine (25.0 g) and2,5-hexanedione (29.0 g) in toluene (150 ml) was added p-toluenesulfonicacid hydrate (4.4 g) at ambient temperature and the mixture was refluxedfor 18 hours. The mixture was evaporated in vacuo and the residue waspurified by column chromatography on silica gel eluting with n-hexane:ethyl acetate (4:1 v/v) to give2-(2,5-dimethyl-1H-pyrrol-1-yl)-6-methylpyridine (35.8 g) as a yellowoil.

[0495]¹H-NMR(DMSO-d₆): δ 2.04(6H, s), 2.51(3H, s), 5.78(2H, s), 7.18(1H,d, J=7.8 Hz), 7.29(1H, d, J=7.6 Hz), 7.86(1H, dd, J=7.8 Hz, 7.6 Hz)APCI-MS(m/z): 187(M+H)⁺

[0496] Preparation 33

[0497] To a solution of diisopropylamine (11.1 g) in tetrahydrofuran (80ml) was added dropwise n-butyllithium (1.59 M solution in hexane, 69.1ml) at -60° C. under a nitrogen atmosphere and the mixture was stirredat −60° C. for 30 minutes. To the mixture was added dropwise a solutionof 2-(2,5-dimethyl-1H-pyrrol-1-yl)-6-methylpyridine (18.63 g) intetrahydrofuran (200 ml) at −60° C. over 50 minutes and the reactionmixture was stirred for 30 minutes. Powdered Dry Ice was added carefullyand the mixture was gradually warmed to ambient temperature. The mixturewas quenched by addition of a saturated aqueous solution of ammoniumchloride and poured into a mixture of ethyl acetate and water. Themixture was adjusted to pH 2 with 6N hydrochloric acid. The separatedorganic layer was washed with water and brine, dried over magnesiumsulfate and evaporated in vacuo. The residue was purified by columnchromatography on silica gel to give[6-(2,5-dimethyl-1H-pyrrol-1-yl)-2-pyridinyl]acetic acid (9.69 g) aspale brown crystals.

[0498] 1H-NMR(DMSO-d₆): δ 2.04(6H, s), 3.79(2H, s), 5.79(2H, s),7.28(2H, d, J=7.9 Hz), 7.38(2H, d, J=7.9 Hz), 7.93(1H, dd, J=7.9 Hz, 7.9Hz), 12.30(1H, br) ESI-MS(m/z): 253(M+Na)⁺, 231(M+H)⁺

[0499] Preparation 34

[0500] To a solution of 5-nitroindoline (4.925 g),[6-(2,5-dimethyl-1H-pyrrol-1-yl)-2-pyridinyl]acetic acid (8.29 g) andPyBOP (benzotriazol-1-yl-oxy-tris-pyrrolidino-phosphoniumhexafluorophosphate (18.7 g) in N,N-dimethylformamide (40 ml) was addeddropwise diisopropylethylamine (7.76 g) at 5° C. The mixture wasgradually warmed to ambient temperature and stirred for 18 hours. Thereaction mixture was poured into a mixture of ethyl acetate and waterand the separated organic layer was washed with water and brine, driedover magnesium sulfate and evaporated in vacuo. The residue was purifiedby column chromatography on silica gel eluting with ethyl acetate togive1-{[6-(2,5-dimethyl-1H-pyrrol-1-yl)-2-pyridinyl]acetyl}-5-nitroindoline(6.67 g) as light yellow crystals.

[0501]¹H-NMR(DMSO-d₆): δ 2.02(6H, s), 3.25(2H, t, J=8.6 Hz), 4.16(2H,s), 4.30(2H, t, J=8.6 Hz), 5.77(2H, s), 7.31(1H, d, J=8.6 Hz), 7.31(1H,d, J=8.6 Hz), 7.98(1H, dd, J=8.6 Hz, 8.6 Hz), 8.00-8.15(3H, m)APCI-MS(m/z): 377(M+H)⁺

[0502] Preparation 35

1-{[6-(2,5-Dimethyl-1H-pyrrol-1-yl)-2-pyridinyl]acetyl}-5-indolinamine

[0503] The title compound was obtained in a similar manner as inPreparation 2 from1-{[6-(2,5-dimethyl-1H-pyrrol-1-yl)-2-pyridinyl]acetyl}-5-nitroindolineas light yellow crystals.

[0504]¹H-NMR(DMSO-d₆): δ 2.22(6H, s), 2.99(2H, t, J=8.4 Hz), 3.98(2H,s), 4.08(2H, t, J=8.4 Hz), 4.84(2H, br s), 5.77(2H, s), 6.32(1H, dd,J=8.5 Hz, 2.2 Hz), 6.45(1H, d, J=2.2 Hz), 7.27(1H, d, J=7.7 Hz),7.39(1H, d, J=7.3 Hz), 7.73(1H, d, J=8.5 Hz), 7.94(1H, dd, J=7.7 Hz, 7.3Hz) ESI-MS (m/z) : 369 (M+Na)⁺, 347 (M+H)⁺

EXAMPLE 20N-(1-{[6-(2,5-Dimethyl-1H-pyrrol-1-yl)-2-pyridinyl]acetyl}-2,3-dihydro-1H-indol-5-yl)-2-(1-piperidinyl)benzamide

[0505] The title compound was obtained in a similar manner as in Example1 from1-{[6-(2,5-dimethyl-1H-pyrrol-1-yl)-2-pyridinyl]acetyl}-5-indolinamineand 2-(1-piperidinyl)benzoic acid.

[0506]¹H-NMR(DMSO-d₆): δ 1.47-1.75(6H, m), 2.03(6H, s), 2.88-2.99(4H,m), 3.17(2H, t, J=8.4 Hz), 4.07(2H, s), 4.20(2H, t, J=8.4 Hz), 5.77(2H,s), 7.16-7.55(6H, m), 7.79-8.07(4H, m), 11.70(1H, s) (+)ESI-MS:534(M+H)⁺, 556(M+Na)⁺

EXAMPLE 21

[0507] A mixture ofN-(1-{[6-(2,5-dimethyl-1H-pyrrol-1-yl)-2-pyridinyl]acetyl}-2,3-dihydro-1H-indol-5-yl)-2-(1-piperidinyl)benzamide(0.45 g), hydroxylamine hydrochloride (0.59 g) and triethylamine (0.24ml) in a mixture of ethanol (18 ml) and water (9 ml) was stirred underreflux for 28 hours. The solvent was removed by concentration. To theresidue was added a mixture of ethyl acetate, tetrahydrofuran and waterand the reaction mixture was adjusted to pH 9 with 20% aqueous potassiumcarbonate solution. The separated organic layer was washed with water,dried over magnesium sulfate and evaporated in vacuo. The residue wastriturated with a mixture of ethyl acetate and tetrahydrofuran to giveN-{1-[(6-amino-2-pyridinyl)acetyl]-2,3-dihydro-1H-indol-5-yl}-2-(1-piperidinyl)benzamide(0.11 g).

[0508]¹H-NMR(DMSO-d₆): δ 1.46-1.82(6H, m), 2.88-3.02(4H, m), 3.17(2H, t,J=8.3 Hz), 3.71(2H, s), 4.21(2H, t, J=8.3 Hz), 5.87(2H, s), 6.31(1H, d,J=8.2 Hz), 6.44(1H, d, J=7.1 Hz), 7.16-7.57(5H, m), 7.77-7.90(2H, m),8.03(1H, d, J=8.6 Hz), 11.68(1H, s) (−)ESI-MS: 454 (M−H)⁻

EXAMPLE 22N-(1-{[6-(2,5-Dimethyl-1H-pyrrol-1-yl)-2-pyridinyl]acetyl}-2,3-dihydro-1H-indol-5-yl)-4-methyl-2-(1-piperidinyl)benzamide

[0509] The title compound was obtained in a similar manner as in Example1 from1-{[6-(2,5-dimethyl-1H-pyrrol-1-yl)-2-pyridinyl]acetyl}-5-indolinamineand 4-methyl-2-(1-piperidinyl)benzoic acid.

[0510]¹H-NMR(DMSO-d₆): δ 1.48-1.80(6H, m), 2.03(6H, s), 2.35(3H, s),2.87-3.00(4H, m), 3.17(2H, t, J=8.3 Hz), 4.07(2H, s), 4.20(2H, t, J=8.3Hz), 5.77(2H, s), 7.05(1H, d, J=8.0 Hz), 7.17(1H, s), 7.30(1H, d, J=7.8Hz), 7.36-7.47(2H, m), 7.78-7.85(2H, m), 7.91-8.06(2H, m), 11.92(1H, s)(+)ESI-MS: 548(M+H)⁺, 570(M+Na)⁺

EXAMPLE 23N-{1-[(6-Amino-2-pyridinyl)acetyl]-2,3-dihydro-1H-indol-5-yl}-4-methyl-2-(1-piperidinyl)benzamide

[0511] The title compound was obtained in a similar manner as in Example21 fromN-(1-{[6-(2,5-dimethyl-1H-pyrrol-1-yl)-2-pyridinyl]acetyl}-2,3-dihydro-1H-indol-5-yl)-4-methyl-2-(1-piperidinyl)benzamide.¹H-NMR(DMSO-d₆): δ 1.46-1.80(6H, m), 2.35(3H, s), 2.84-3.00(4H, m),3.16(2H, t, J=8.3 Hz), 3.71(2H, s), 4.21(2H, t, J=8.3 Hz), 5.87(2H, s),6.31(1H, d, J=8.1 Hz), 6.44(1H, d, J=7.2 Hz), 7.05(1H, d, J=7.9 Hz),7.17(1H, s), 7.26-7.46(2H, m), 7.75-7.87(2H, m), 8.03(1H, d, J=8.6 Hz),11.90(1H, s) (−)ESI-MS: 468(M−H)⁻

[0512] Preparation 36

[0513] 2-Nitrobenzoyl chloride (0.88 g) was added to a mixture of1-(2-pyridinylacetyl)-5-indolinamine (1.0 g) and triethylamine (0.66 ml)in N,N-dimethylformamide (15 ml) under ice-cooling and the mixture wasstirred at ambient temperature for 4 hours. The mixture was poured intoa mixture of water and ethyl acetate and the mixture was adjusted to pH9 with 20% aqueous potassium carbonate solution. The resultantprecipitate was collected by filtration to give2-nitro-N-[1-(2-pyridinylacetyl)-2,3-dihydro-1H-indol-5-yl]benzamide(1.00 g).

[0514]¹H-NMR(DMSO-d₆): δ 3.18(2H, t, J=8.3 Hz), 4.02(2H, s), 4.23(2H, t,J=8.3 Hz), 7.23-7.42(3H, s), 7.65(1H, s), 7.69-7.93(4H, m), 8.00(1H, d,J=8.7 Hz), 8.14(1H, d, J=7.8 Hz), 8.47-8.55(1H, m), 10.61(1H, s)(−)ESI-MS: 401(M−H)⁻

[0515] Preparation 37

[0516] To a mixture of2-nitro-N-[1-(2-pyridinylacetyl)-2,3-dihydro-1H-indol-5-yl]benzamide(0.8 g) in a mixture of methanol (30 ml) and tetrahydrofuran (30 ml) wasadded 10% palladium on carbon (0.4 g, 50% wet). The reaction mixture wasstirred at ambient temperature for 5 hours under hydrogen atmosphere.The catalyst was filtered off and the solvent was removed byconcentration. The residue was triturated with a mixture of diethylether and ethyl acetate to give2-amino-N-[1-(2-pyridinylacetyl)-2,3-dihydro-1H-indol-5-yl]benzamide(3.52 g).

[0517]¹H-NMR(DMSO-d₆): δ 3.16(2H, t, J=8.3 Hz), 4.01(2H, s), 4.22(2H, t,J=8.3 Hz), 6.31(2H, s), 6.53-6.63(1H, m), 6.70-6.77(1H, m),7.14-7.32(2H, m), 7.33-7.47(2H, m), 7.60(1H, dd, J=1.1 Hz, 7.9 Hz),7.66(1H, s), 7.77(1H, dt, J=1.8 Hz, 7.6 Hz), 7.98(1H, d, J=8.7 Hz),8.48-8.54(1H, m), 9.93(1H, s) (−) ESI-MS: 371 (M−H)⁻

EXAMPLE 242-(Dimethylamino)-N-[1-(2-pyridinylacetyl)-2,3-dihydro-1H-indol-5-yl]benzamide

[0518] The title compound was obtained in a similar manner as in Example1 from 1-(2-pyridinylacetyl)-5-indolinamine and 2-(dimethylamino)benzoicacid.

[0519]¹H-NMR(DMSO-d₆): δ 2.77(6H, s), 3.17(2H, t, J=8.4 Hz), 4.01(2H,s), 4.22(2H, t, J=8.4 Hz), 7.04-7.15(1H, m), 7.18-7.50(5H, m),7.64-7.83(3H, m), 8.00(1H, d, J=8.7 Hz), 8.47-8.54(1H, m), 11.25(1H, s)(+)APCI-MS: 401(M+H)⁺

[0520] Preparation 38

[0521] To a mixture of 2-amino-4-methylbenzoic acid (3.0 g) and 37%aqueous formaldehyde (29.7 ml) in methanol (60 ml) was added 10%palladium on carbon (2.0 g, 50% wet). The reaction mixture was stirredat ambient temperature for 16 hours under hydrogen atmosphere. Thecatalyst was filtered off and the solvent was removed by concentrationand the residue was triturated with ethyl acetate to give2-(dimethylamino)-4-methylbenzoic acid (1.91 g).

[0522]¹H-NMR(DMSO-d₆): δ 2.38(3H, s), 2.80(6H, s), 7.20(1H, d, J=7.9Hz), 7.56(1H, s), 7.88(1H, d, J=7.9 Hz) (+)ESI-MS: 180(M+H)⁺, 202(M+Na)⁺

EXAMPLE 252-(Dimethylamino)-4-methyl-N-[1-(2-pyridinylacetyl)-2,3-dihydro-1H-indol-5-yl]benzamide

[0523] The title compound was obtained in a similar manner as in Example1 from 1-(2-pyridinylacetyl)-5-indolinamine and2-(dimethylamino)-4-methylbenzoic acid.

[0524]¹H-NMR(DMSO-d₆): δ 2.34(3H, s), 2.76(6H, s), 3.17(2H, t, J=8.3Hz), 4.01(2H, s), 4.22(2H, t, J=8.3 Hz), 6.95(1H, t, J=8.0 Hz), 7.10(1H,s), 7.24-7.47(3H, m), 7.64-7.82(3H, m), 8.00(1H, d, J=8.6 Hz),8.48-8.53(1H, m), 11.50(1H, s) (+)ESI-MS: 415(M+H)⁺, 437(M+Na)⁺

[0525] Preparation 39

[0526] A mixture of 2-chloro-6-methylnicotinic acid (3.43 g), tert-butyl5-amino-1-indolinecarboxylate (5.15 g), 1-hydroxybenzotriazole hydrate(3.21 g) and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide (3.26 g) inN,N-dimethylformamide (30 ml) was stirred at ambient temperatureovernight. The reaction mixture was poured into a mixture of ethylacetate and water, and the organic layer was washed with brine and driedover magnesium sulfate. The solvent was evaporated in vacuo and theresidue was chromatographed on silica gel eluting with ethyl acetate andn-hexane (6:4 v/v). The eluted fractions containing the desired productwere collected and evaporated in vacuo to give tert-butyl5-{[(2-chloro-6-methyl-3-pyridinyl)carbonyl]amino}-1-indolinecarboxylate(6.65 g).

[0527]¹H-NMR(DMSO-d₆): δ 1.51(9H, s), 2.51(3H, s), 3.07(2H, t, J=8.5Hz), 3.91(2H, t, J=8.5 Hz), 7.37-7.41(2H, m), 7.52-7.69(2H, m), 7.92(1H,d, J=7.6 Hz), 10.43 (1H, s)

[0528] Preparation 40

[0529] A mixture of tert-butyl5-{[(2-chloro-6-methyl-3-pyridinyl)carbonyl]amino}-1-indolinecarboxylate(1.55 g) and piperidine (1.6 ml) in tetrahydrofuran (10 ml) was refluxedunder stirring for 4.5 hours. The reaction mixture was poured into amixture of ethyl acetate and water, and the organic layer was washedwith brine and dried over magnesium sulfate. The solvent wasconcentrated in vacuo and the precipitate was collected by filtration togive tert-butyl5-({[6-methyl-2-(1-piperidinyl)-3-pyridinyl]carbonyl}amino)-1-indolinecarboxylate(1.01 g).

[0530]¹H-NMR(DMSO-d₆): δ 1.51(9H, s), 1.51-1.53(6H, m), 2.40(3H, s),3.35(2H, t, J=8.4 Hz), 3.35(4H, m), 3.90(2H, t, J=8.4 Hz), 6.83(1H, d,J=7.7 Hz), 7.40-7.43(2H, m), 7.67(1H, s), 7.75(1H, d, J=7.6 Hz),10.47(1H, s) (+)ESI-MS(m/z): 437(M+H)⁺, 459(M+Na)⁺

[0531] Preparation 41

[0532] A mixture of tert-butyl5-({[6-methyl-2-(1-piperidinyl)-3-pyridinyl]carbonyl}amino)-1-indolinecarboxylate(1.0 g) and trifluoroacetic acid (1.8 ml) in dichloromethane (5 ml) wasstirred at ambient temperature for 5 hours. The reaction mixture wasevaporated in vacuo. The residue was dissolved in a mixture of ethylacetate and water and the mixture was adjusted to pH 8.5 with aqueouspotassium carbonate solution. The organic layer was washed with brineand dried over magnesium sulfate. The solvent was concentrated in vacuoand the precipitate was collected by filtration to giveN-(2,3-dihydro-1H-indol-5-yl)-6-methyl-2-(1-piperidinyl)nicotinamide(595 mg).

[0533]¹H-NMR(DMSO-d₆): δ 1.52-1.58(6H, m), 2.39(3H, s), 2.90(2H, t,J=8.4 Hz), 3.19-3.21(4H, m), 3.35-3.42(2H, m), 5.35(1H, s), 6.46(1H, d,J=8.3 Hz), 6.83(1H, d, J=7.6 Hz), 7.20(1H, d, J=8.3 Hz), 7.417(1H, s),7.75(1H, d, J=7.6 Hz), 10.29(1H, s)

EXAMPLE 26

[0534] A mixture ofN-(2,3-dihydro-1H-indol-5-yl)-6-methyl-2-(1-piperidinyl)nicotinamide(330 mg), 2-pyridylacetic acid dihydrochloride (179 mg),1-hydroxybenzotriazole hydrate (158 mg),1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide (160 mg) andN,N-dimethylaminopyridine (2.4 mg) in N,N-dimethylformamide (15 ml) wasstirred at ambient temperature overnight. The reaction mixture waspoured into a mixture of ethyl acetate and water, and the organic layerwas washed with brine and dried over magnesium sulfate. The solvent wasconcentrated in vacuo and the precipitate was collected by filtration togive6-methyl-2-(1-piperidinyl)-N-[1-(2-pyridinylacetyl)-2,3-dihydro-1H-indol-5-yl]nicotinamide(305 mg).

[0535]¹H-NMR(DMSO-d₆): δ 1.53(6H, br,s), 2.39(3H, s), 3.13-3.55(8H, m),4.01(2H, s), 4.22(2H, t, J=8.30 Hz), 6.83(1H, d, J=7.64 Hz),7.24-7.43(3H, m), 7.73-7.81(3H, m), 7.89(1H, d, J=8.66 Hz),8.48-8.51(1H, m), 10.52(1H, s) (+)ESI-MS(m/z): 456(M+H)⁺, 478(M+Na)⁺

[0536] Preparation 42

tert-Butyl5-({[6-methyl-2-(4-methyl-1-piperidinyl)-3-pyridinyl]carbonyl}amino)-1-indolinecarboxylate

[0537] The title compound was obtained in a similar manner as inPreparation 40 from tert-butyl5-{[(2-chloro-6-methyl-3-pyridinyl)carbonyl]amino}-1-indolinecarboxylateand 4-methylpiperidine.

[0538]¹H-NMR(DMSO-d₆): δ 0.98(3H, d, J=6.2 Hz), 1.13-1.28(2H, m),1.40(9H, s), 1.40-1.65(3H, m), 2.39(3H, s), 2.74-2.80(2H, m), 3.10(2H,t, J=8.4 Hz), 3.60-3.68(2H, m), 3.90(2H, t, J=8.4 Hz), 6.82(1H, d, J=7.6Hz), 7.39-7.42(1H, m), 7.42-7.67(1H, m), 7.67(1H, s), 7.74(1H, d, J=7.6Hz), 10.44(1H, s) (+)ESI-MS(m/z): 451(M+H)⁺, 473(M+Na)⁺

[0539] Preparation 43

N-(2,3-Dihydro-1H-indol-5-yl)-6-methyl-2-(4-methyl-1-piperidinyl)nicotinamide

[0540] The title compound was obtained in a similar manner as inPreparation 41 from tert-butyl5-({[6-methyl-2-(4-methyl-1-piperidinyl)-3-pyridinyl]carbonyl}amino)-1-indolinecarboxylate.

[0541]¹H-NMR(DMSO-d₆): δ 0.90(3H, d, J=6.1 Hz), 1.18-1.31(2H, m),1.46-1.66(3H, m), 2.38(3H, s), 2.74-2.94(4H, m), 3.33-3.44(2H, m),3.60-3.67(2H, m), 5.34(1H, s), 6.46(1H, d, J=8.2 Hz), 6.82(1H, d, J=7.6Hz), 7.20(1H, dd, J=1.9 Hz, 8.2 Hz), 7.46(1H, d, J=1.9 Hz), 7.74(1H, d,J=7.6 Hz), 10.24(1H, s) (+)ESI-MS(m/z): 351(M+H)⁺, 373(M+Na)⁺

EXAMPLE 276-Methyl-2-(4-methyl-1-piperidinyl)-N-[1-(2-pyridinylacetyl)-2,3-dihydro-1H-indol-5-yl]nicotinamide

[0542] The title compound was obtained in a similar manner as in Example26 fromN-(2,3-dihydro-1H-indol-5-yl)-6-methyl-2-(4-methyl-1-piperidinyl)nicotinamideand 2-pyridylacetic acid dihydrochloride.

[0543]¹H-NMR(DMSO-d₆): δ 0.88(3H, d, J=6.1 Hz), 1.14-1.21(2H, m),1.52-1.70(3H, m), 2.39(3H, s), 2.70-2.80(2H, m), 3.17-3.21(2H, m),3.61-3.68(2H, m), 4.00(2H, s), 4.12-4.22(2H, m), 6.82(1H, d, J=7.6 Hz),7.28-7.42(3H, m), 7.72-7.77(3H, m), 7.98 (1H, d, J=8.7 Hz),8.49-8.52(1H, m), 10.47(1H, s) (+)ESI-MS(m/z): 470(M+1)⁺, 492(M+Na)⁺

[0544] Preparation 44

[0545] A mixture of 2-chloro-nicotinic acid (1.58 g),1-(2-pyridinylacetyl)-5-indolinamine (2.67 g), 1-hydroxybenzotriazolehydrate (1.61 g) and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide(1.63 g) in N,N-dimethylformamide (30 ml) was stirred at ambienttemperature overnight. The reaction mixture was poured into a mixture ofethyl acetate and water and stirred at ambient temperature for 20minutes. The precipitate was collected by filtration and washedsuccessively with water, ethyl acetate and diisopropyl ether and driedto give2-chloro-N-[1-(2-pyridinylacetyl)-2,3-dihydro-1H-indol-5-yl]nicotinamide(2.95 g).

[0546]¹H-NMR(DMSO-d₆): δ 3.18(2H, t, J=8.32 Hz), 4.01(2H, s), 4.23(2H,t, J=8.32 Hz), 7.25-7.39(1H, m), 7.52-7.59(2H, m), 7.68-7.69(1H, m),7.76-7.77(2H, m), 7.97-8.08(2H, m), 8.49-8.54(2H, m), 10.57(1H, s)

EXAMPLE 28

[0547] A mixture of2-chloro-N-[1-(2-pyridinylacetyl)-2,3-dihydro-1H-indol-5-yl]nicotinamide(432 mg) and piperidine (0.45 ml) in chloroform (20 ml) was refluxedunder stirring for 12 hours. The reaction mixture was poured into amixture of chloroform and water and the organic layer was washed withbrine and dried over magnesium sulfate. The solvent was evaporated invacuo and the residue was chromatographed on silica gel eluting withchloroform and methanol (97:3 v/v). The fractions containing the desiredproduct were collected and concentrated in vacuo and the precipitate wascollected by filtration to give2-(1-piperidinyl)-N-[1-(2-pyridinylacetyl)-2,3-dihydro-1H-indol-5-yl]nicotinamide(335 mg).

[0548]¹H-NMR(DMSO-d6): δ 1.53(6H, s), 3.22-3.25(4H, m), 4.01(2H, s),6.90-6.98(1H, m), 7.21-7.43(3H, m), 7.70-7.82(3H, m), 7.96-8.02(1H, m),8.23-8.26(1H, m), 8.45-8.47(1H, m), 10.46(1H, s) (+)ESI-MS (m/z) :442(M+H)⁺, 464(M+Na)⁺

EXAMPLE 292-(4-Methyl-1-piperidinyl)-N-[1-(2-pyridinylacetyl)-2,3-dihydro-1H-indol-5-yl]nicotinamide

[0549] The title compound was obtained in a similar manner as in Example28 from2-chloro-N-[1-(2-pyridinylacetyl)-2,3-dihydro-1H-indol-5-yl]nicotinamideand 4-methylpiperidine.

[0550]¹H-NMR(DMSO-d₆): δ 0.87(3H, d, J=6.1 Hz), 1.14-1.21(2H, m),1.21-1.64(3H, m), 2.76-2.88(2H, m), 3.17(2H, t, J=8.3 Hz), 3.66-3.73(2H,m), 4.01(2H, s), 4.22(2H, t, J=8.3 Hz), 6.90-6.96(1H, m), 7.28-7.34(3H,m), 7.72-7.82(3H, m), 7.98(1H, d, J=8.6 Hz), 8.26-8.29(1H, m),8.49-8.51(1H, m), 10.45(1H, s) (+)ESI-MS(m/z): 456(M+H)⁺, 478(M+Na)⁺

[0551] Preparation 45

2-Chloro-N-(2,3-dihydro-1H-indol-5-yl)-6-methylnicotinamide

[0552] The title compound was obtained in a similar manner as inPreparation 41 from tert-butyl5-{[(2-chloro-6-methyl-3-pyridinyl)carbonyl]amino}-1-indolinecarboxylate.

[0553]¹H-NMR(DMSO-d₆): δ 2.50(3H, s), 2.90(2H, t, J=8.3 Hz),3.34-3.45(2H, m), 5.39(1H, s), 6.46(1H, d, J=8.3 Hz), 7.18(1H, dd, J=1.9Hz, 8.3 Hz), 7.35-7.40(2H, m), 7.88(1H, d, J=7.6 Hz), 10.13(1H, s)

[0554] Preparation 46

2-Chloro-6-methyl-N-[1-(2-pyridinylacetyl)-2,3-dihydro-1H-indol-5-yl]nicotinamide

[0555] The title compound was obtained in a similar manner as inPreparation 41 from2-chloro-N-(2,3-dihydro-1H-indol-5-yl)-6-methylnicotinamide and2-pyridylacetic acid dihydrochloride.

[0556]¹H-NMR(DMSO-d₆): δ 2.50(3H, s), 3.20(2H, t, J=8.3 Hz), 3.96(2H,s), 4.23(2H, t, J=8.3 Hz), 7.27-7.28(1H, m), 7.36-7.41(3H, m), 7.67 (1H,s), 7.74-7.78(1H, m), 7.98-8.00(1H, m), 8.80(1H, d, J=3.4 Hz), 10.46(1H,s)

EXAMPLE 306-Methyl-N-[1-(2-pyridinylacetyl)-2,3-dihydro-1H-indol-5-yl]-2-(4-morpholinyl)nicotinamide

[0557] The title compound was obtained in a similar manner as in Example28 from2-chloro-6-methyl-N-[1-(2-pyridinylacetyl)-2,3-dihydro-1H-indol-5-yl]nicotinamideand morpholine.

[0558]¹H-NMR(DMSO-d₆) : δ 2.49(3H, s), 3.13-3.34(6H, m) , 3.61-3.66(4H,m), 3.94(2H, s), 4.22(2H, t, J=8.3 Hz), 6.85(1H, d, J=7.6 Hz),7.25-7.45(3H, m), 7.71-7.81(3H, m), 7.94-8.17(1H, m), 8.80(1H, d, J=3.9Hz), 10.39(1H, s) (+)ESI-MS(m/z): 458(M+H)⁺, 480(M+Na)⁺

EXAMPLE 31

[0559] A mixture ofN-(2,3-dihydro-1H-indol-5-yl)-6-methyl-2-(1-piperidinyl)nicotinamide(286 mg), {6-[(tert-butoxycarbonyl)amino]-2-pyridinyl}acetic acid (225mg), 1-hydroxybenzotriazole hydrate (137 mg,1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide (139 mg) andN,N-dimethylaminopyridine (2.4 mg) in N,N-dimethylformamide (15 ml) wasstirred at ambient temperature overnight. The reaction mixture waspoured into a mixture of ethyl acetate and water, and the organic layerwas washed with brine and dried over magnesium sulfate. The solvent wasevaporated in vacuo and the residue was chromatographed on silica geleluting with ethyl acetate and n-hexane (7:3 v/v). The fractionscontaining the desired product were collected and evaporated in vacuo togive tert-butyl6-{2-[5-({[6-methyl-2-(1-piperidinyl)-3-pyridinyl]carbonyl}amino)-2,3-dihydro-1H-indol-1-yl]-2-oxoethyl}-2-pyridinylcarbamate(470 mg).

[0560]¹H-NMR(DMSO-d₆): δ 1.46(9H, s), 1.53(6H, br.s), 2.39(3H, s),3.14-3.33(6H, m), 6.83(1H, d, J=7.7 Hz), 6.96-7.00(1H, m), 7.37-7.42(1H,m), 7.67-7.77(4H, m), 7.98(1H, d, J=8.7 Hz), 9.67(1H, s), 10.52(1H, s)

EXAMPLE 32

[0561] A mixture of tert-butyl6-{2-[5-({[6-methyl-2-(1-piperidinyl)-3-pyridinyl]carbonyl}amino)-2,3-dihydro-1H-indol-1-yl]-2-oxoethyl}-2-pyridinylcarbamate(460 mg) and trifluoroacetic acid (0.6 ml) in dichloromethane (5 ml) wasstirred at ambient temperature for 5 hours. The reaction mixture wasevaporated in vacuo and the residue was dissolved in a mixture of ethylacetate and water and adjusted to pH 8.5 with aqueous potassiumcarbonate solution. The organic layer was washed with brine and driedover magnesium sulfate. The solvent was concentrated in vacuo and theprecipitate was collected by filtration to giveN-{1-[(6-amino-2-pyridinyl)acetyl]-2,3-dihydro-1H-indol-5-yl}-6-methyl-2-(1-piperidinyl)nicotinamide(306 mg).

[0562]¹H-NMR(DMSO-d₆): δ 1.53(6H, br.s), 2.39(3H, s), 3.11-3.30(6H, m),4.20(2H, t, J=8.3 Hz), 5.86(2H, s), 6.30(1H, d, J=7.9 Hz), 6.43(1H, d,J=7.0 Hz), 6.83(1H, d, J=7.6 Hz), 7.28-7.43(2H, m), 7.72-7.78(2H, m),7.98(1H, d, J=8.7 Hz), 10.51(1H, s) (+)ESI-MS(m/z): 471(M+H)⁺

[0563] Preparation 47

[0564] A mixture of tert-butyl5-{[(2-chloro-6-methyl-3-pyridinyl)carbonyl]amino}-1-indolinecarboxylate(3.1 g) in 2M dimethylamine-tetrahydrofuran solution (20 ml) wasrefluxed under stirring for 10 hours. The reaction mixture was pouredinto a mixture of ethyl acetate and water, and the organic layer waswashed with brine and dried over magnesium sulfate. The solvent wasconcentrated in vacuo and the precipitate was collected by filtration togive tert-butyl5-({[2-(dimethylamino)-6-methyl-3-pyridinyl]carbonyl}amino)-1-indolinecarboxylate(2.19 g).

[0565]¹H-NMR(DMSO-d₆): δ 1.51(9H, s), 2.36(3H, s), 2.94(6H, s), 3.05(2H, t, J=8.4 Hz), 3.90(2H, t, J=8.4 Hz), 6.61(1H, d, J=7.5 Hz),7.39-7.43(1H, m), 7.54-7.60(3H, m), 10.18(1H, s) (+)ESI-MS(m/z):397(M+H)⁺, 419(M+Na)⁺

[0566] Preparation 48

N-(2,3-Dihydro-1H-indol-5-yl)-2-(dimethylamino)-6-methylnicotinamide

[0567] The title compound was obtained in a similar manner as inPreparation 41 from tert-butyl5-({[2-(dimethylamino)-6-methyl-3-pyridinyl]carbonyl}amino)-1-indolinecarboxylate.

[0568]¹H-NMR(DMSO-d₆): δ 2.35(3H, s), 2.89(2H, t, J=8.4 Hz), 2.94(6H,s), 3.39(2H, t, J=8.4 Hz), 5.33(1H, s), 6.43(1H, d, J=7.5 Hz), 6.60(1H,d, J=7.5 Hz), 7.18(1H, m), 7.40(1H, s), 7.53(1H, d, J=7.4 Hz), 9.90(1H,s) (+)ESI-MS(m/z): 297(M+H)⁺

EXAMPLE 33 tert-Butyl6-{2-[5-({[2-(dimethylamino)-6-methyl-3-pyridinyl]carbonyl}amino)-2,3-dihydro-1H-indol-1-yl]-2-oxoethyl}-2-pyridinylcarbamate

[0569] The title compound was obtained in a similar manner as in Example31 fromN-(2,3-dihydro-1H-indol-5-yl)-2-(dimethylamino)-6-methylnicotinamide and{6-[(tert-butoxycarbonyl)amino]-2-pyridinyl}acetic acid.

[0570]¹H-NMR(DMSO-d₆): δ 1.46(9H, s), 2.36(3H, s), 2.89(6H, s), 3.17(2H,t, J=8.3 Hz), 3.86(2H, s), 4.27(2H, t, J=8.3 Hz), 6.61(1H, d, J=7.5 Hz),6.96-7.00(1H, m), 7.35-7.40(1H, m), 7.57(1H, d, J=7.5 Hz), 7.64-7.69(2H,m), 7.94-7.98(2H, m), 9.67(1H, s), 10.23(1H, s) (+)ESI-MS(m/z):531(M+H)⁺, 553(M+Na)⁺

EXAMPLE 34N-{1-[(6-Amino-2-pyridinyl)acetyl]-2,3-dihydro-1H-indol-5-yl}-2-(dimethylamino)-6-methylnicotinamide

[0571] The title compound was obtained in a similar manner as in Example32 from tert-butyl6-(2-[5-({[2-(dimethylamino)-6-methyl-3-pyridinyl]carbonyl}amino)-2,3-dihydro-1H-indol-1-yl]-2-oxoethyl}-2-pyridinylcarbamate.

[0572]¹H-NMR(DMSO-d₆): δ 2.35(3H, s), 2.94(6H, s), 3.14(2H, t, J=8.4Hz), 3.71(2H, s), 4.19(2H, t, J=8.4 Hz), 5.87(2H, s), 6.31(1H, d, J=8.2Hz), 6.43(1H, d, J=7.2 Hz), 6.61 (1H, d, J=7.5 Hz), 7.30-7.40(2H, m),7.57(1H, d, J=7.5 Hz), 7.66(1H, s), 7.98(1H, d, J=8.7 Hz), 10.22(1H, s)(+)ESI-MS(m/z): 431(M+H)⁺, 453(M+Na)⁺

EXAMPLE 352-(Dimethylamino)-6-methyl-N-[1-(2-pyridinylacetyl)-2,3-dihydro-1H-indol-5-yl]nicotinamide

[0573] The title compound was obtained in a similar manner as in Example26 fromN-(2,3-dihydro-1H-indol-5-yl)-2-(dimethylamino)-6-methylnicotinamide and2-pyridylacetic acid dihydrochloride.

[0574]¹H-NMR(DMSO-d6): δ 2.37(3H, s), 2.95(6H, s), 3.19(2H, t, J=8.4Hz), 3.92(2H, s), 3.93(2H, t, J=8.4 Hz), 6.63(1H, d, J=7.6 Hz),7.51-7.62(2H, m), 7.73-7.82(2H, m), 7.91(1H, d, J=8.6 Hz), 8.11-8.23(2H,m), 8.79-8.81(1H, m), 10.34(1H, s)

EXAMPLE 36

[0575] 1-[3-(Dimethylamino)propyl]-3-ethylcarbodiimide (0.19 g) wasadded to a solution of N-(4-aminophenyl)-2-(2-pyridinyl)acetamide (0.23g), 4-methyl-2-(4-methyl-1-piperidinyl)benzoic acid (0.28 g),1-hydroxybenzotriazole hydrate (0.16 g) and 4-dimethylaminopyridine (6mg) in dichloromethane (5 ml) under ice-cooling and the mixture wasstirred at ambient temperature for 18 hours. The reaction mixture waspoured into a mixture of ethyl acetate and water. The separated organiclayer was washed with water, dried over magnesium sulfate and evaporatedin vacuo. The residue was triturated with ethyl acetate to give4-methyl-2-(4-methyl-1-piperidinyl)-N-{4-[(2-pyridinylacetyl)amino]phenyl}benzamide(0.14 g).

[0576]¹H-NMR(DMSO-d₆): δ 0.95(3H, d, J=6.0 Hz), 1.20-1.62(3H, m),1.67-1.82(2H, m), 2.35(3H, s), 2.69-2.87(2H, m), 3.04-3.17(2H, m),3.84(2H, s), 7.04(1H, d, J=7.9 Hz), 7.17(1H, s), 7.23-7.32(1H, m),7.41(1H, d, J=7.8 Hz), 7.60(2H, d, J=9.1 Hz), 7.69(2H, d, J=9.1 Hz),7.69-7.86(2H, m), 8.48-8.54(1H, m), 10.23(1H, s), 11.87(1H, s)(+)ESI-MS: 443(M+H)⁺, 465(M+Na)⁺

EXAMPLE 372-(Dimethylamino)-4-methyl-N-{4-[(2-pyridinylacetyl)amino]phenyl}benzamide

[0577] The title compound was obtained in a similar manner as in Example36 from N-(4-aminophenyl)-2-(2-pyridinyl)acetamide and2-(dimethylamino)-4-methylbenzoic acid.

[0578]¹H-NMR(DMSO-d₆): δ 2.34(3H, s), 2.76(6H, s), 3.84(2H, s), 6.95(1H,d, J=7.8 Hz), 7.10(1H, s), 7.22-7.32(1H, m), 7.40(1H, d, J=7.8 Hz),7.53-7.83(6H, m), 8.47-8.54(1H, m), 10.22(1H, s), 11.51(1H, s)(+)ESI-MS: 389(M+H)⁺, 411(M+Na)⁺

[0579] Preparation 49

[0580] To a solution of 4-fluoronitrobenzene (12.71 g) and2-(2-pyridinyl)ethylamine (12.22 g) in N,N-dimethylformamide (70 ml) wasadded triethylamine (10.12 g) at ambient temperature and the mixture wasstirred at 60° C. for 16 hours. The mixture was cooled to 5° C. andpoured into a mixture of ethyl acetate and water. The separated organiclayer was washed with water and brine, dried over magnesium sulfate andevaporated in vacuo. The residue was triturated with diisopropyl ether,collected by filtration, washed with diisopropyl ether and dried invacuo to give 2-[2-(4-nitroanilino)ethyl]pyridine (21.21 g) as a yellowsolid.

[0581]¹H-NMR(DMSO-d₆): δ 3.02(2H, t, J=7.0 Hz), 3.55(2H, td, J=7.0 Hz,5.6 Hz), 6.65(2H, d, J=9.3 Hz), 7.24(1H, dd, J=7.8 Hz, 4.9 Hz), 7.31(1H,d, J=7.8 Hz), 7.39(1H, t, J=5.6 Hz), 7.65-7.8(1H, m), 7.98(1H, d, J=9.3Hz), 8.52(1H, d, J=4.0 Hz) APCI-MS(m/z): 244(M⁺+1)

[0582] Preparation 50

[0583] To a solution of 2-[2-(4-nitroanilino)ethyl]pyridine (17.87 g) intetrahydrofuran (150 ml) were added di-tert-butyl dicarbonate (19.25 g)and triethylamine (8.92 g) at ambient temperature and the mixture wasrefluxed for 16 hours. The mixture was evaporated in vacuo and theresidue was purified by column chromatography on silica gel eluting withhexane: ethyl acetate (2:1 v/v) to give tert-butyl4-nitrophenyl[2-(2-pyridinyl)ethyl]carbamate (18.21 g) as a yellowsolid.

[0584]¹H-NMR(DMSO-d₆): δ 1.37(9H, s), 2.95(2H, t, J=8.0 Hz), 4.09(2H, t,J=8.0 Hz), 7.2-7.3(2H, m), 7.52(2H, d, J=9.1 Hz), 7.65-7.75(1H, m),8.17(2H, d, J=9.1 Hz), 8.23(1H, d, J=4.8 Hz) APCI-MS(m/z): 344(M⁺+1)

[0585] Preparation 51

[0586] To a suspension of tert-butyl4-nitrophenyl[2-(2-pyridinyl)ethyl]carbamate (20.03 g) in ethanol (400ml) were added iron(III) chloride (anhydrous) (189 mg) andactive-charcoal (20 g) and the mixture was heated to 80° C. To themixture was added dropwise hydrazine hydrate (11.67 g) and the mixturewas stirred at 80° C. for 4 hours. The active-charcoal was filtered offby celite and washed with ethanol. The filtrate was evaporated in vacuoand the residue was purified by column chromatography on silica geleluting with ethyl acetate to give tert-butyl4-aminophenyl[2-(2-pyridinyl)ethyl]carbamate (15.03 g) as a light brownsolid.

[0587]¹H-NMR(DMSO-d₆): δ 1.29(9H, s), 2.86(2H, t, J=7.0 Hz), 3.78(2H, t,J=7.0 Hz), 5.04(2H, br s), 6.52 (2H, d, J=8.5 Hz), 6.80(2H, d, J=8.5Hz), 7.15-7.3(2H, m), 7.65-7.75(1H, m), 8.45(1H, d, J=4.2 Hz)APCI-MS(m/z): 314(M+H)⁺

EXAMPLE 38

[0588] 1-[3-(Dimethylamino)propyl]-3-ethylcarbodiimide (0.19 g) wasadded to a solution of tert-butyl4-aminophenyl[2-(2-pyridinyl)ethyl]carbamate (0.31 g),4-methyl-2-(1-pyrrolidinyl)benzoic acid (0.25 g), 1-hydroxybenzotriazolehydrate (0.16 g) and 4-dimethylaminopyridine (6 mg) in dichloromethane(5 ml) under ice-cooling and the mixture was stirred at ambienttemperature for 18 hours. To the reaction mixture was added a solutionof 10% hydrogen chloride in methanol (9 ml) and the mixture was stirredat ambient temperature for 20 hours. The reaction mixture was pouredinto a mixture of ethyl acetate and water, and the mixture was adjustedto pH 9 with 20% aqueous potassium carbonate solution. The separatedorganic layer was washed with water, dried over magnesium sulfate andevaporated in vacuo. The residue was purified by column chromatographyon silica gel using a mixture of ethyl acetate and diisopropyl ether(1:1 v/v) as an eluant. The eluted fractions containing the desiredproduct were collected and evaporated in vacuo to give4-methyl-N-(4-{[2-(2-pyridinyl)ethyl]amino}phenyl)-2-(1-pyrrolidinyl)benzamide(0.18 g).

[0589]¹H-NMR(DMSO-d₆): δ 1.77-1.93(4H, m), 2.27(3H, s), 2.98(2H, t,J=7.2 Hz), 3.14-3.28(4H, m), 3.28-3.43(2H, m), 5.51(1H, t, J=5.7 Hz),6.50-6.64(4H, m), 7.13-7.27(2H, m), 7.31(1H, d, J=7.8 Hz), 7.41(2H, d,J=8.7 Hz), 7.71(1H, dt, J=1.7 Hz, 7.6 Hz), 8.49-8.55(1H, m), 9.91(1H, s)(+)ESI-MS: 401(M+H)⁺, 423(M+Na)⁺

EXAMPLE 394-Methyl-2-(1-piperidinyl)-N-(4-{[2-(2-pyridinyl)ethyl]amino}phenyl)benzamide

[0590] The title compound was obtained in a similar manner as in Example38 from tert-butyl 4-aminophenyl[2-(2-pyridinyl)ethyl]carbamate and4-methyl-2-(1-piperidinyl)benzoic acid.

[0591]¹H-NMR(DMSO-d₆): δ 1.47-1.80(6H, m), 2.34(3H, s), 2.85-3.07(6H,m), 3.31-3.44(2H, m), 5.59(1H, t, J=5.7 Hz), 6.61(2H, d, J=8.8 Hz),7.04(1H, d, J=8.0 Hz), 7.14-7.28(2H, m), 7.33(1H, d, J=7.8 Hz), 7.49(2H,d, J=8.8 Hz), 7.71(1H, dt, J=1.8 Hz, 7.6 Hz), 7.84(1H, d, J=8.0 Hz),8.49-8.56(1H, m), 11.77(1H, s) (+)ESI-MS: 415(M+H)⁺, 437(M+Na)⁺

EXAMPLE 402-(Hexahydro-1H-azepin-1-yl)-4-methyl-N-(4-{[2-(2-pyridinyl)ethyl]amino}phenyl)benzamide

[0592] The title compound was obtained in a similar manner as in Example38 from tert-butyl 4-aminophenyl[2-(2-pyridinyl)ethyl]carbamate and2-(hexahydro-1H-azepin-1-yl)-4-methylbenzoic acid.

[0593]¹H-NMR(DMSO-d₆): δ 1.52-1.67(4H, m), 1.67-1.85(4H, m), 2.31(3H,s), 2.98(2H, t, J=7.2 Hz), 3.12-3.27(4H, m), 3.29-3.44(2H, m), 5.56(1H,t, J=5.7 Hz), 6.59(2H, d, J=8.8 Hz), 6.86(1H, d, J=7.7 Hz), 7.03(1H, s),7.17-7.28(1H, m), 7.32(1H, d, J=7.7 Hz), 7.42(2H, d, J=8.8 Hz), 7.58(1H,d, J=7.7 Hz), 7.65-7.77(1H, m), 8.48-8.56(1H, m), 11.19(1H, s)(+)ESI-MS: 429(M+H)⁺, 451(M+Na)⁺

EXAMPLE 414-Methyl-2-(4-methyl-1-piperidinyl)-N-(4-{[2-(2-pyridinyl)ethyl]amino}phenyl)benzamide

[0594] The title compound was obtained in a similar manner as in Example38 from tert-butyl 4-aminophenyl[2-(2-pyridinyl)ethyl]carbamate and4-methyl-2-(4-methyl-1-piperidinyl)benzoic acid.

[0595]¹H-NMR(DMSO-d₆): δ 0.97(3H, d, J=6.4 Hz), 1.29-1.41(2H, m),1.47-1.59(1H, m), 1.71-1.79(2H, m), 2.34(3H, s), 2.73-2.82(2H, m),2.99(2H, t, J=7.3 Hz), 3.06-3.12(2H, m), 3.32-3.42(2H, m), 5.58(1H, t,J=5.7 Hz), 6.61(2H, d, J=8.8 Hz), 7.03(1H, d, J=7.9 Hz), 7.16(1H, s),7.20-7.26(1H, m), 7.33(1H, d, J=7.9 Hz), 7.48(2H, d, J=8.8 Hz),7.68-7.74(1H, m), 7.83(1H, d, J=7.9 Hz), 8.50-8.55(1H, m), 11.70(1H, s)(+)ESI-MS: 429(M+H)⁺, 451(M+Na)⁺

EXAMPLE 422-(Dimethylamino)-4-methyl-N-(4-{[2-(2-pyridinyl)ethyl]amino}phenyl)benzamide

[0596] The title compound was obtained in a similar manner as in Example38 from tert-butyl 4-aminophenyl[2-(2-pyridinyl)ethyl]carbamate and2-(dimethylamino)-4-methylbenzoic acid.

[0597]¹H-NMR(DMSO-d₆): δ 2.33(3H, s), 2.75(6H, s), 2.99(2H, t, J=7.2Hz), 3.30-3.44(2H, m), 5.56(1H, t, J=5.7 Hz), 6.59(2H, d, J=8.8 Hz),6.94(1H, d, J=8.0 Hz), 7.08(1H, s), 7.18-7.27(1H, m), 7.32(1H, d, J=7.8Hz), 7.43(2H, d, J=8.8 Hz), 7.64-7.77(2H, m), 8.49-8.55(1H, m),11.18(1H, s) (+)ESI-MS: 375(M+H)⁺, 397(M+Na)⁺

[0598] Preparation 52

[0599] A mixture of 2-chloro-6-methylnicotinic acid (3.43 g), tert-butyl4-aminophenyl[2-(2-pyridinyl)ethyl]carbamate (5.15 g),1-hydroxybenzotriazole hydrate (3.21 g) and1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide (3.26 g) inN,N-dimethylformamide (30 ml) was stirred at ambient temperatureovernight. The reaction mixture was poured into a mixture of ethylacetate and water, and the organic layer was washed with brine and driedover magnesium sulfate. The solvent was evaporated in vacuo and theresidue was chromatographed on silica gel eluting with ethyl acetate andn-hexane (5:5 v/v). The fractions containing the desired product werecollected and evaporated in vacuo to give tert-butyl4-{[(2-chloro-6-methyl-3-pyridinyl)carbonyl]amino}phenyl[2-(2-pyridinyl)ethyl]carbamate(8.43 g).

[0600]¹H-NMR(DMSO-d₆): δ 1.18(9H, s), 2.35(3H, s), 2.27(2H, t, J=7.3Hz), 3.79(2H, t, J=7.3 Hz), 7.03-7.11(4H, m), 7.26(1H, d, J=7.8 Hz),7.50-7.58(3H, m), 7.81(1H, d, J=7.6 Hz), 8.31-8.33(1H, m), 10.47(1H, s)

EXAMPLE 43

[0601] A mixture of tert-butyl4-{[(2-chloro-6-methyl-3-pyridinyl)carbonyl]amino}phenyl[2-(2-pyridinyl)ethyl]carbamate(700 mg) and piperidine (0.5 ml) in tetrahydrofuran (10 ml) was refluxedunder stirring for 5 hours. The reaction mixture was poured into amixture of ethyl acetate and water, and the organic layer was washedwith brine and dried over magnesium sulfate. The solvent was evaporatedin vacuo and the residue was chromatographed on silica gel eluting withethyl acetate and n-hexane (5:5 v/v). The fractions containing thedesired product were collected and evaporated in vacuo to givetert-butyl4-({[6-methyl-2-(1-piperidinyl)-3-pyridinyl]carbonyl}amino)phenyl[2-(2-pyridinyl)ethyl]carbamate(520 mg).

[0602]¹H-NMR(DMSO-d₆): δ 1.32(9H, s), 1.55-1.57(6H, m), 2.40(3H, s),2.91(2H, t, J=7.4 Hz), 3.22-3.33(4H, m), 3.91(2H, t, J=7.4 Hz), 6.84(1H,d, J=7.6 Hz), 7.16-7.25(4H, m), 7.64-7.71(3H, m), 7.77(1H, d, J=7.6 Hz),8.45-8.46(1H, m), 10.62(1H, s)

EXAMPLE 44

[0603] A mixture of tert-butyl4-({[6-methyl-2-(1-piperidinyl)-3-pyridinyl]carbonyl}amino)phenyl[2-(2-pyridinyl)ethyl]carbamate(520 mg) and trifluoroacetic acid (1.0 ml) in dichloromethane (5 ml) wasstirred at ambient temperature for 5 hours. The reaction mixture wasevaporated in vacuo. The residue was dissolved in a mixture of ethylacetate and water, and the mixture was adjusted to pH 8.5 with aqueouspotassium carbonate solution. The organic layer was washed with brineand dried over magnesium sulfate. The solvent was concentrated in vacuoand the precipitate was collected by filtration to give6-methyl-2-(1-piperidinyl)-N-(4-{[2-(2-pyridinyl)ethyl]amino}phenyl)nicotinamide(398 mg).

[0604]¹H-NMR(DMSO-d₆): δ 1.52-1.58(6H, m), 2.39(3H, s), 2.99(2H, t,J=7.4 Hz), 3.18-3.21(4H, m), 3.34-3.39(2H, m), 5.55-5.58(1H, m),6.59(2H, d, J=8.8 Hz), 6.84 (1H, d, J=7.6 Hz), 7.21-7.24(1H, m),7.32(1H, d, J=7.8 Hz), 7.45(2H, d, J=8.8 Hz), 7.69-7.73(1H, m), 7.77(1H,d, J=7.6 Hz), 8.51-8.52(1H, m), 10.33 (1H, s) (+)ESI-MS(m/z) :416(M+H)⁺, 438(M+Na)⁺

EXAMPLE 45 tert-Butyl4-({[6-methyl-2-(4-methyl-1-piperidinyl)-3-pyridinyl]carbonyl}amino)phenyl[2-(2-pyridinyl)ethyl]carbamate

[0605] The title compound was obtained in a similar manner as in Example43 from tert-butyl4-{[(2-chloro-6-methyl-3-pyridinyl)carbonyl]amino}phenyl[2-(2-pyridinyl)ethyl]carbamateand 4-methylpiperidine.

[0606]¹H-NMR(DMSO-d6): δ 0.89(3H, d, J=6.1 Hz), 1.14-1.46(2H, m),1.47(9H, s), 1.50-1.52(1H, m), 1.60-1.66(2H, m), 2.40(3H, s),2.76-2.95(4H, m), 3.64-3.70(2H, m), 3.88-3.97(2H, m), 6.82(1H, d, J=7.7Hz), 7.15-7.26(4H, m), 7.65-7.78(4H, m), 8.44-8.47(1H, m), 10.57(1H, s)

EXAMPLE 466-Methyl-2-(4-methyl-1-piperidinyl)-N-(4-{[2-(2-pyridinyl)ethyl]amino}phenyl)nicotinamide

[0607] The title compound was obtained in a similar manner as in Example44 from tert-butyl4-({[6-methyl-2-(4-methyl-1-piperidinyl)-3-pyridinyl]carbonyl}amino}phenyl[2-(2-pyridinyl)ethyl]carbamate.

[0608]¹H-NMR(DMSO-d₆): δ 0.90(6H, d, J=6.5 Hz), 1.17-1.26(2H, m),1.49-1.51(1H, m), 1.62-1.65(2H, m), 2.39(3H, s), 2.99(2H, t, J=7.4 Hz),3.34-3.39(2H, m), 3.61-3.65(2H, m), 5.56-5.59(1H, m), 6.58(2H, d, J=8.9Hz), 6.82(1H, d, J=7.6 Hz), 7.21-7.24(1H, m), 7.32(1H, d, J=7.8 Hz),7.45(2H, d, J=8.9 Hz), 7.69-7.76(2H, m), 8.51-8.52(1H, m), 10.26(1H, s)(+)ESI-MS(m/z): 430(M+H)⁺, 452(M+Na)⁺

EXAMPLE 47 tert-Butyl4-({[6-methyl-2-(4-thiomorpholinyl)-3-pyridinyl]carbonyl}amino)phenyl[2-(2-pyridinyl)ethyl]carbamate

[0609] The title compound was obtained in a similar manner as in Example43 from tert-butyl4-{[(2-chloro-6-methyl-3-pyridinyl)carbonyl]amino}phenyl[2-(2-pyridinyl)ethyl]carbamateand thiomorpholine.

[0610]¹H-NMR(DMSO-d₆): δ 1.32(9H, s), 2.41(3H, s), 2.63-2.68(4H, m),2.91(2H, t, J=7.4 Hz), 3.52-3.57(4H, m), 3.91(2H, t, J=7.4 Hz), 6.85(1H,d, J=7.7 Hz), 7.15-7.26(4H, m), 7.65-7.75(4H, m), 8.44-8.47(1H, m),10.42(1H, s)

EXAMPLE 486-Methyl-N-(4-{[2-(2-pyridinyl)ethyl]amino}phenyl)-2-(4-thiomorpholinyl)nicotinamide

[0611] The title compound was obtained in a similar manner as in Example44 from tert-butyl4-({[6-methyl-2-(4-thiomorpholinyl)-3-pyridinyl]carbonyl}amino)phenyl[2-(2-pyridinyl)ethyl]carbamate.

[0612]¹H-NMR(DMSO-d₆): δ 2.39(3H, s), 2.63-2.68(4H, m), 2.98(2H, t,J=7.4 Hz), 3.33-3.40(2H, m), 3.50-3.55(4H, m), 5.60(1H, s), 6.59(2H, d,J=8.8 Hz), 6.86 (1H, d, J=7.6 Hz), 7.19-7.26(1H, m), 7.32(1H, d, J=7.6Hz), 7.44(2H, d, J=8.8 Hz), 7.67-7.75(2H, m), 8.50-8.53(1H, m),10.05(1H, s) (+)ESI-MS(m/z): 434(M+H)⁺, 456(M+Na)⁺

EXAMPLE 49 tert-Butyl4-({[6-methyl-2-(4-morpholinyl)-3-pyridinyl]carbonyl}amino)phenyl[2-(2-pyridinyl)ethyl]carbamate

[0613] The title compound was obtained in a similar manner as in Example43 from tert-butyl4-{[(2-chloro-6-methyl-3-pyridinyl)carbonyl]amino}phenyl[2-(2-pyridinyl)ethyl]carbamateand morpholine.

[0614]¹H-NMR(DMSO-d₆): δ 1.29(9H, s), 2.48(3H, s), 2.91(2H, t, J=7.4Hz), 3.23-3.28(4H, m), 3.63-3.67(4H, m), 3.96(2H, t, J=7.4 Hz), 6.86(1H,d, J=7.7Hz), 7.15-7.26(4H, m), 7.65-7.77(4H, m), 8.45-8.47(1H, m),10.49(1H, s)

EXAMPLE 506-Methyl-N-(4-{[2-(2-pyridinyl)ethyl]amino}phenyl)-2-(4-morpholinyl)nicotinamide

[0615] The title compound was obtained in a similar manner as in Example44 from tert-butyl4-{[(2-chloro-6-methyl-3-pyridinyl)carbonyl]amino}phenyl[2-(2-pyridinyl)ethyl]carbamate.

[0616]¹H-NMR(DMSO-d₆): δ 2.40(3H, s), 2.98(2H, t, J=7.4 Hz),3.21-3.26(4H, m), 3.33-3.40(4H, m), 3.66-3.68(2H, m), 5.58(1H, br.s),6.58(2H, d, J=8.9 Hz), 6.85(1H, d, J=7.7 Hz), 7.19-7.26(1H, m), 7.32(1H,d, J=7.7 Hz), 7.45(2H, d, J=8.9 Hz), 7.67-7.75(2H, m), 8.50-8.53(1H, m),10.11(1H, s) (+)ESI-MS(m/z): 418(M+H)⁺, 440(M+Na)⁺

[0617] Preparation 53

tert-Butyl4-{[(2-chloro-3-pyridinyl)carbonyl]amino}-phenyl[2-(2-pyridinyl)ethyl]carbamate

[0618] The title compound was obtained in a similar manner as inPreparation 52 from 2-chloronicotinic acid and tert-butyl4-aminophenyl[2-(2-pyridinyl)ethyl]carbamate.

[0619]¹H-NMR(DMSO-d₆): δ 1.29(9H, s), 2.90(2H, t, J=7.4 Hz), 3.92(2H, t,J=7.4 Hz), 7.20-7.26(4H, m), 7.56-7.59(1H, m), 7.66-7.70(3H, m),8.08-8.10(1H, m), 8.54-8.55(1H, m), 10.69(1H, s)

EXAMPLE 51 tert-Butyl4-({[2-(1-piperidinyl)-3-pyridinyl]carbonyl}amino)phenyl[2-(2-pyridinyl)ethyl]carbamate

[0620] The title compound was obtained in a similar manner as in Example43 from tert-butyl4-{[(2-chloro-6-methyl-3-pyridinyl)carbonyl]amino}phenyl[2-(2-pyridinyl)ethyl]carbamateand piperidine.

[0621]¹H-NMR(DMSO-d₆): δ 1.32(9H, s), 1.55(6H, s), 2.91(2H, t, J=7.4Hz), 3.26(4H, s), 3.91(2H, t, J=7.4 Hz), 6.95(1H, dd, J=4.7 Hz, 7.4 Hz),7.16-7.27(4H, m), 7.66-7.72(3H, m), 7.81-7.85(1H, m), 8.28-8.31(1H, m),8.46(1H, d, J=4.1 Hz), 10.57(1H, s)

EXAMPLE 522-(1-Piperidinyl)-N-(4-{[2-(2-pyridinyl)ethyl]amino}phenyl)nicotinamide

[0622] The title compound was obtained in a similar manner as in Example44 from tert-butyl4-({[2-(1-piperidinyl)-3-pyridinyl]carbonyl}amino)phenyl[2-(2-pyridinyl)ethyl]carbamate.

[0623]¹H-NMR(DMSO-d₆): δ 1.52-1.58(6H, m), 2.39(3H, s), 2.99(2H, t,J=7.4 Hz), 3.18-3.21(4H, m), 3.34-3.39(2H, m), 5.55-5.58(1H, m),6.59(2H, d, J=8.8 Hz), 6.84(1H, d, J=7.6 Hz), 7.21-7.24(1H, m), 7.32(1H,d, J=7.8 Hz), 7.45(2H, d, J=8.8 Hz), 7.69-7.73(1H, m), 7.77(1H, d, J=7.6Hz), 8.51-8.52(1H, m), 10.33(1H, s) (+)ESI-MS(m/z): 402(M+H)⁺,424(M+Na)⁺

EXAMPLE 53 tert-Butyl4-({[2-(4-methyl-1-piperidinyl)-3-pyridinyl]carbonyl}amino)phenyl[2-(2-pyridinyl)ethyl]carbamate

[0624] The title compound was obtained in a similar manner as in Example43 from tert-butyl4-{[(2-chloro-6-methyl-3-pyridinyl)carbonyl]amino}phenyl[2-(2-pyridinyl)ethyl]carbamateand 4-methylpiperidine.

[0625]¹H-NMR(DMSO-d₆): δ 0.89(3H, d, J=6.1 Hz), 1.21(9H, s),1.14-1.18(2H, m), 1.21-1.32(3H, m), 2.78-2.95(4H, m), 3.69-3.75(2H, m),3.92(2H, t, J=7.4Hz), 6.93-6.97(1H, m), 7.16-7.26(4H, m), 7.65-7.70(3H,m), 7.71-7.84(1H, m), 8.27-8.31(1H, m), 8.45-8.47(1H, m), 10.54(1H, s)

EXAMPLE 542-(4-Methyl-1-piperidinyl)-N-(4-{[2-(2-pyridinyl)ethyl]amino}phenyl)nicotinamide

[0626] The title compound was obtained in a similar manner as in Example44 from tert-butyl4-({[2-(4-methyl-1-piperidinyl)-3-pyridinyl]carbonyl}amino)phenyl[2-(2-pyridinyl)ethyl]carbamate.

[0627]¹H-NMR(DMSO-d₆): δ 0.87(3H, d, J=6.2 Hz), 1.05-1.30(2H, m),1.35-1.66(3H, m), 2.76-2.87(2H, m), 2.99(2H, t, J=7.3 Hz), 3.33-3.41(2H,m), 3.66-3.72(2H, m), 5.63(1H, br.s), 6.59(2H, d J=8.8 Hz),6.90-6.96(1H, m), 7.23-7.26(1H, m), 7.33(1H, d, J=7.7 Hz), 7.44(2H, d,J=8.8 Hz), 7.68-7.83(2H, m), 8.25-8.28(1H, m), 8.50-8.53(1H, m),10.21(1H, s) (+)ESI-MS(m/z): 416(M+H)⁺, 438(M+Na)⁺

EXAMPLE 55

[0628] A mixture of tert-butyl4-{[(2-chloro-6-methyl-3-pyridinyl)carbonyl]amino}phenyl[2-(2-pyridinyl)ethyl]carbamate(700 mg) in 2M dimethylamine-tetrahydrofuran solution (10 ml) wasstirred at 65-70° C. for 10 hours. The reaction mixture was poured intoa mixture of ethyl acetate and water, and the organic layer was washedwith brine and dried over magnesium sulfate. The solvent wasconcentrated in vacuo and the precipitate was collected by filtration togive tert-butyl4-({[2-(dimethylamino)-6-methyl-3-pyridinyl]carbonyl}amino)-phenyl[2-(2-pyridinyl)ethyl]carbamate(460 mg).

[0629]¹H-NMR(DMSO-d₆): δ 1.33(9H, s), 2.37(3H, s), 2.90(2H, t, J=7.4Hz), 2.96(6H, s), 3.91(2H, t, J=7.4 Hz), 6.62(1H, d, J=7.6 Hz),7.15-7.25(4H, m), 7.60(1H, d, J=7.6 Hz), 7.66-7.69(3H, m), 8.46-8.47(1H,m), 10.35(1H, s)

EXAMPLE 562-(Dimethylamino)-6-methyl-N-(4-{[2-(2-pyridinyl)ethyl]amino}phenyl)nicotinamide

[0630] The title compound was obtained in a similar manner as in Example44 from tert-butyl4-({[2-(dimethylamino)-6-methyl-3-pyridinyl]carbonyl}amino)phenyl[2-(2-pyridinyl)ethyl]carbamate.

[0631]¹H-NMR(DMSO-d₆): δ 2.35(3H, s), 2.94(6H, s), 3.00(2H, t, J=7.40Hz), 3.35-3.39(2H, m), 6.57-6.61(3H, m), 7.24-7.34(1H, m), 7.35(1H, d,J=7.8 Hz), 7.41(2H, d, J=8.8 Hz), 7.55 (1H, d, J=7.5 Hz), 7.72-7.76(1H,m), 8.52-8.54(1H, m), 9.94(1H, s) (+)ESI-MS(m/z): 376(M+H)⁺, 398(M+Na)⁺

EXAMPLE 57

[0632] tert-Butyl4-({[2-(dimethylamino)-3-pyridinyl]carbonyl}amino)phenyl[2-(2-pyridinyl)ethyl]carbamate

[0633] The title compound was obtained in a similar manner as in Example55 from tert-butyl4-{[(2-chloro-3-pyridinyl)carbonyl]amino}phenyl[2-(2-pyridinyl)ethyl]carbamateand dimethylamine.

[0634]¹H-NMR(DMSO-d₆): δ 1.33(9H, s), 2.90(2H, t, J=7.4 Hz), 2.97(6H,s), 3.91(2H, t, J=7.4 Hz), 6.72-6.78(1H, m), 7.15-7.26(4H, m),7.65-7.74(4H, m), 8.19-8.22(1H, m), 8.45-8.48(1H, m), 10.42(1H, s)

EXAMPLE 582-(Dimethylamino)-N-(4-{[2-(2-pyridinyl)ethyl]amino}-phenyl)nicotinamide

[0635] The title compound was obtained in a similar manner as in Example44 from tert-butyl4-({[2-(dimethylamino)-3-pyridinyl]carbonyl}amino)phenyl[2-(2-pyridinyl)ethyl]carbamate.

[0636]¹H-NMR(DMSO-d₆): δ 2.98(2H, t, J=7.4 Hz), 2.96(6H, s),3.34-3.40(2H, m), 6.57(2H, d, J=8.8 Hz), 6.70-6.76(1H, m), 7.23-7.33(2H,m), 7.41(2H, d, J=8.8 Hz), 7.60-7.71(2H, m), 8.16-8.18(1H, m), 8.52(1H,d, J=4.0 Hz), 9.99(1H, s) (+)ESI-MS(m/z): 362(M+H)⁺, 384(M+Na)⁺

[0637] Preparation 54

2-Chloro-6-methyl-N-(4-{[2-(2-pyridinyl)ethyl]amino}-phenyl)nicotinamide

[0638] The title compound was obtained in a similar manner as in Example44 from tert-butyl4-{[(2-chloro-6-methyl-3-pyridinyl)carbonyl]amino}phenyl[2-(2-pyridinyl)ethyl]carbamate.

[0639]¹H-NMR(DMSO-d₆): δ 2.49(3H, s), 2.98(2H, t, J=7.4 Hz),3.33-3.42(2H, m), 5.62(1H, t, J=5.7 Hz), 6.58(2H, d, J=8.9 Hz),7.20-7.43(5H, m), 7.67-7.71(1H, m), 7.89(1H, d, J=7.7 Hz), 8.50-8.53(1H,m), 10.14(1H, s) (+)ESI-MS(m/z): 367(M+H)⁺, 389(M+Na)⁺

[0640] Preparation 55

[0641] A mixture of 2-chloro-6-methylnicotinic acid (2.06 g),4-[2-(2-pyridinyl)ethoxy]phenylamine (2.70 g), 1-hydroxybenzotriazolehydrate (1.93 g) and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide(1.96 g) in N,N-dimethylformamide (30 ml) was stirred at ambienttemperature overnight. The reaction mixture was poured into a mixture ofethyl acetate and water, and the organic layer was washed with brine anddried over magnesium sulfate. The solvent was evaporated in vacuo andthe residue was chromatographed on silica gel eluting with ethyl acetateand n-hexane (7:3-9:1 v/v). The fractions containing the desired productwere collected and evaporated in vacuo to give2-chloro-6-methyl-N-{4-[2-(2-pyridinyl)ethoxy]phenyl}nicotinamide (2.95g). ¹H-NMR(DMSO-d₆): δ 2.49(3H, s), 3.19(2H, t, J=6.6 Hz), 4.34(2H, t,J=6.6 Hz), 6.92-6.94(2H, m), 7.24-7.25(1H, m), 7.37-7.42(2H, m),7.58-7.60(2H, m), 7.72-7.74(1H, m), 7.93(1H, d, J=7.7 Hz), 8.52-8.53(1H,m), 10.41(1H, s) (+)ESI-MS(m/z): 368(M+H)⁺, 390(M+Na)⁺

EXAMPLE 59

[0642] A mixture of2-chloro-6-methyl-N-{4-[2-(2-pyridinyl)ethoxy]phenyl}nicotinamide (440mg) and piperidine (0.5 ml) in tetrahydrofuran (10 ml) was refluxedunder stirring for 5 hours. The reaction mixture was poured into amixture of ethyl acetate and water, and the organic layer was washedwith brine and dried over magnesium sulfate. The solvent was evaporatedin vacuo and the residue was chromatographed on silica gel eluting withethyl acetate and n-hexane (7:3 v/v). The fractions containing thedesired product were collected and concentrated in vacuo and theprecipitate was collected by filtration to give6-methyl-2-(1-piperidinyl)-N-{4-[2-(2-pyridinyl)ethoxy]phenyl}nicotinamide(425 mg).

[0643]¹H-NMR(DMSO-d₆): δ 1.53(6H, br.s), 2.39(3H, s), 3.18(2H, t, J=6.6Hz), 4.33(2H, t, J=6.6 Hz), 6.82(1H, d, J=7.6 Hz), 6.92(2H, d, J=9.0Hz), 7.21-7.28(1H, m), 7.37(1H, d, J=7.8 Hz), 7.62(2H, d, J=9.0 Hz),7.69-7.77(2H, m), 8.50-8.53(1H, m), 10.44(1H, s) (+)ESI-MS(m/z):417(M+H)⁺, 439(M+Na)⁺

EXAMPLE 606-Methyl-2-(4-methyl-1-piperidinyl)-N-{4-[2-(2-pyridinyl)ethoxy]phenyl}nicotinamide

[0644] The title compound was obtained in a similar manner as in Example44 from2-chloro-6-methyl-N-{4-[2-(2-pyridinyl)ethoxy]phenyl}nicotinamide and4-methylpiperidine.

[0645]¹H-NMR(DMSO-d₆): δ 0.88(3H, d, J=6.2 Hz), 1.14-1.25(2H, m),1.28-1.61(3H, m), 2.39 (3H, s), 2.52-2.86(2H, m), 3.18 (2H, t, J=6.6Hz), 3.62-3.68(2H, m), 4.33(2H, t, J=6.6 Hz), 6.81(1H, d, J=7.6 Hz),6.92(2H, d, J=9.0 Hz), 7.23-7.28(1H, m), 7.37(1H, d, J=7.7Hz), 7.62(2H,d, J=9.0 Hz), 7.69-7.77(2H, m), 8.50-8.53(1H, m), 10.40(1H, s)(+)ESI-MS(m/z): 431(M+H)⁺, 453(M+Na)⁺

EXAMPLE 61

[0646] A mixture of2-chloro-6-methyl-N-{4-[2-(2-pyridinyl)ethoxy]phenyl}nicotinamide (736mg) in 2M dimethylamine-tetrahydrofuran solution (10 ml) was stirred at65-70° C. for 10 hours. The reaction mixture was poured into a mixtureof ethyl acetate and water, and the organic layer was washed with brineand dried over magnesium sulfate. The solvent was evaporated in vacuoand the residue was chromatographed on silica gel eluting with ethylacetate and n-hexane (7:3 v/v). The fractions containing the desiredproduct were collected and concentrated in vacuo and the precipitate wascollected by filtration to give2-(dimethylamino)-6-methyl-N-{4-[2-(2-pyridinyl)ethoxy]phenyl}-nicotinamide(205 mg).

[0647]¹H-NMR(DMSO-d₆): δ 2.35(3H, s), 3.14(6H, s), 3.29(2H, t, J=6.7Hz), 4.33(2H, t, J=6.7 Hz), 6.61(1H, d, J=7.5 Hz), 6.90(2H, d, J=9.0Hz), 7.21-7.28(1H, dm), 7.36(1H, d, J=7.7 Hz), 7.54-7.60(3H, m),7.69-7.77(1H, m), 8.50-8.52(1H, m), 10.14(1H, s) (+)ESI-MS (m/z) : 377(M+H)⁺, 399 (M+Na)⁺

[0648] Preparation 56

2-Chloro-N-{4-[2-(2-pyridinyl)ethoxy]phenyl}nicotinamide

[0649] The title compound was obtained in a similar manner as inPreparation 55 from 2-chloronicotinic acid and4-[2-(2-pyridinyl)ethoxy]phenylamine.

[0650]¹H-NMR(DMSO-d₆): δ 3.19(2H, t, J=6.6 Hz), 4.34(2H, t, J=6.6 Hz),6.94(2H, d, J=9.0 Hz), 7.25-7.28(1H, m), 7.39(1H, d, J=7.8 Hz),7.54-7.61(3H, m), 7.74-7.76(1H, m), 8.04-8.07(1H, m), 8.51-8.53(2H, m),10.49(1H, s) (+)ESI-MS(m/z): 354(M+H)⁺, 376(M+Na)⁺

EXAMPLE 622-(1-Piperidinyl)-N-{4-[2-(2-pyridinyl)ethoxy]phenyl}-nicotinamide

[0651] The title compound was obtained in a similar manner as in Example59 from N-{4-[2-(2-pyridinyl)ethoxy]phenyl}nicotinamide and piperidine.

[0652]¹H-NMR(DMSO-d₆): δ 1.53(6H, br.s), 3.15-3.24(6H, m), 4.34(2H, t,J=6.6 Hz), 6.90-6.97(3H, m), 7.37(1H, d, J=7.7Hz), 7.63(2H, d, J=9.0Hz), 7.69-7.83(2H, m), 8.16-8.29(1H, m), 8.51-8.53(1H, m), 10.40(1H, s)(+)ESI-MS(m/z) : 403(M+H)⁺, 425(M+Na)⁺

EXAMPLE 632-(4-Methyl-1-piperidinyl)-N-{4-[2-(2-pyridinyl)ethoxy]-phenyl}nicotinamide

[0653] The title compound was obtained in a similar manner as in Example59 from N-{4-[2-(2-pyridinyl)ethoxy]phenyl}nicotinamide and4-methylpiperidine.

[0654]¹H-NMR(DMSO-d₆): δ 0.88(3H, d, J=6.1 Hz), 1.02-1.27(2H, m),1.30-1.64(3H, m), 2.76-2.88(2H, m), 3.19(2H, t, J=6.6 Hz), 3.68-3.74(2H,m), 4.34(2H, t, J=6.6 Hz), 6.90-6.95(3H, m), 7.24-7.25(1H, m), 7.37(1H,d, J=7.7 Hz), 7.62-7.83(4H, m), 8.26-8.29(1H, m), 8.51-8.53(1H, m),10.39(1H, s) (+) ESI-MS (m/z): 417 (M+H)⁺, 439 (M+Na)⁺

[0655] Preparation 57

[0656] 2-Chloro-5-nitropyridine (4.76 g) was added portionwise to asolution of 2-hydroxyethylpyridine (4.43 g) and potassium tert-butoxide(4.04 g) in tetrahydrofuran (60 ml). The mixture was stirred at atemperature between 5 and 20° C. under ice-cooling and the resultantmixture was stirred at ambient temperature for 3 hours. The reactionmixture was poured into a mixture of ethyl acetate and water. Theorganic layer was washed with 5% aqueous potassium carbonate solutionand brine and dried over magnesium sulfate. The solvent was evaporatedin vacuo and the residue was chromatographed on silica gel eluting withethyl acetate: n-hexane (5:5 v/v). The fractions containing the desiredproduct were collected and concentrated in vacuo and the precipitate wascollected by filtration to give5-nitro-2-[2-(2-pyridinyl)ethoxy]pyridine (2.42 g).

[0657]¹H-NMR(DMSO-d₆): δ 3.24(2H, t, J=6.68 Hz), 4.80(2H, t, J=6.68 Hz),6.98(1H, d, J=9.16 Hz), 7.24-7.28(1H, m), 7.35(1H, d, J=7.78 Hz),7.69-7.77(1H, m), 8.42-8.52(2H, m), 9.09(1H, d, J=2.86 Hz)

[0658] Preparation 58

[0659] A mixture of 5-nitro-2-[2-(2-pyridinyl)ethoxy]pyridine (736 mg),iron powder (900 mg) and ammonium chloride (101 mg) in ethanol (40 ml)and water (8 ml) was refluxed under stirring for 2.5 hours. Afterremoval of the insoluble materials by filtration, the solvent wasevaporated in vacuo and the residue was dissolved in ethyl acetate andwater. The organic layer was washed with brine and dried over magnesiumsulfate. The solvent was evaporated in vacuo to give6-[2-(2-pyridinyl)ethoxy]-3-pyridinamine (664 mg).

[0660] Preparation 59

2-Chloro-6-methyl-N-{6-[2-(2-pyridinyl)ethoxy]-3-pyridinyl}nicotinamide

[0661] The title compound was obtained in a similar manner as inPreparation 55 from 2-chloro-6-methylnicotinic acid and6-[2-(2-pyridinyl)ethoxy]-3-pyridinamine.

[0662]¹H-NMR(DMSO-d₆): δ 2.50(3H, s), 3.19(2H, t, J=6.8 Hz), 4.34(2H, t,J=6.8Hz), 6.80(1H, d, J=8.9 Hz), 7.23-7.43(3H, m), 7.68-7.73(1H, m),7.95-8.01(2H, m), 8.45-8.53(2H, m), 10.61(1H, s)

EXAMPLE 646-Methyl-2-(4-methyl-1-piperidinyl)-N-{6-[2-(2-pyridinyl)ethoxy]-3-pyridinyl}nicotinamide

[0663] The title compound was obtained in a similar manner as in Example59 from2-chloro-6-methyl-N-{6-[2-(2-pyridinyl)ethoxy]-3-pyridinyl}nicotinamideand 4-methylpiperidine.

[0664]¹H-NMR(DMSO-d₆): δ 0.89(3H, d, J=6.2 Hz), 1.06-1.30(2H, m),1.32-1.72(3H, m), 2.39(3H, s), 2.72-2.90(2H, m), 3.18(2H, t, J=6.7 Hz),3.65-3.70(2H, m), 4.60(2H, t, J=6.7 Hz), 6.76-6.81(2H, m), 7.32-7.36(2H,m), 7.71-7.75(2H, m), 7.97-8.03(1H, m), 8.47-8.51(2H, m), 10.46(1H, s)(+)ESI-MS(m/z): 432(M+H)⁺, 454(M+Na)⁺

EXAMPLE 652-(Dimethylamino)-6-methyl-N-{6-[2-(2-pyridinyl)ethoxy]-3-pyridinyl}nicotinamide

[0665] The title compound was obtained in a similar manner as in Example61 from2-chloro-6-methyl-N-{6-[2-(2-pyridinyl)ethoxy]-3-pyridinyl}nicotinamideand dimethylamine.

[0666]¹H-NMR(DMSO-d₆): δ 2.36(3H, s), 2.95(6H, s), 3.18(2H, t, J=6.7Hz), 4.61(2H, t, J=6.7 Hz), 6.62(1H, d, J=7.5 Hz), 6.77(1H, d, J=8.9Hz), 7.20-7.26(1H, m), 7.34(1H, d, J=7.8 Hz), 7.68-7.76(1H, m),7.95-8.00(1H, m), 8.46-8.52(2H, m), 10.30(1H, s) (+)ESI-MS(m/z):378(M+H)⁺, 400(M+Na)⁺

[0667] Preparation 60

[0668] A mixture of 2-chloro-6-methylnicotinic acid (772 mg),3-{[4-(4-aminophenyl)-1-piperazinyl]methyl}benzonitrile (1.38 g),1-hydroxybenzotriazole hydrate (723 mg) and1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide (733 mg) inN,N-dimethylformamide (15 ml) was stirred at ambient temperatureovernight. The reaction mixture was poured into a mixture of ethylacetate and water, and the organic layer was washed with brine and driedover magnesium sulfate. The solvent was concentrated in vacuo and theprecipitate was collected by filtration to give2-chloro-N-{4-[4-(3-cyanobenzyl)-1-piperazinyl]phenyl}-6-methylnicotinamide(1.69 g).

[0669]¹H-NMR(DMSO-d₆): δ 2.51(3H, s), 2.51-2.54(4H, m), 3.09-3.11(4H,m), 3.60(2H, s), 6.92(2H, d, J=9.0 Hz), 7.38(1H, d, J=7.8 Hz),7.60-7.68(3H, m), 7.72-7.76(3H, m), 7.91(1H, d, J=7.7 Hz), 10.31(1H, s)(+)ESI-MS(m/z): 446(M+H)⁺, 468(M+Na)⁺

EXAMPLE 66

[0670] A mixture of2-chloro-N-{4-[4-(3-cyanobenzyl)-1-piperazinyl]phenyl}-6-methylnicotinamide(400 mg) and 4-methylpiperidine (0.5 ml) in tetrahydrofuran (5 ml) wasrefluxed under stirring for 12 hours. The reaction mixture was pouredinto a mixture of ethyl acetate and water, and the organic layer waswashed with brine and dried over magnesium sulfate. The solvent wasconcentrated in vacuo and the precipitate was collected by filtration togiveN-{4-[4-(3-cyanobenzyl)-1-piperazinyl]phenyl}-6-methyl-2-(4-methyl-1-piperidinyl)nicotinamide(380 mg).

[0671]¹H-NMR(DMSO-d₆): δ 0.90(3H, d, J=6.2 Hz), 1.17-1.24(2H, m),1.27-1.69(3H, m), 2.39(3H, s), 2.50-2.52(4H, m), 2.75-2.86(2H, m),3.09-3.10(4H, m), 3.59(2H, s), 3.59-3.67(2H, m), 6.82(1H, d, J=7.7 Hz),6.92(2H, d, J=9.0 Hz), 7.53-7.60(3H, m), 7.68-7.77(4H, m), 10.39(1H, s)(+)ESI-MS(m/z) : 509(M+H)⁺, 531(M+Na)⁺

EXAMPLE 67

[0672] A mixture of2-chloro-N-{4-[4-(3-cyanobenzyl)-1-piperazinyl]phenyl}-6-methylnicotinamide(400 mg) in 2M dimethylamine-tetrahydrofuran solution (10 ml) wasstirred at 65-70° C. for 10 hours. The reaction mixture was poured intoa mixture of ethyl acetate and water, and the organic layer was washedwith brine and dried over magnesium sulfate. The solvent was evaporatedin vacuo and the residue was chromatographed on silica gel eluting withethyl acetate and n-hexane (7:3 v/v). The fractions containing thedesired product were collected and concentrated in vacuo and theprecipitate was collected by filtration to giveN-{4-[4-(3-cyanobenzyl)-1-piperazinyl]phenyl}-2-(dimethylamino)-6-methylnicotinamide(90 mg).

[0673]¹H-NMR(DMSO-d₆): δ 2.35(3H, s), 2.49-2.54(4H, m), 2.94(6H, s),3.07-3.09(4H, m), 3.59(2H, s), 6.60(1H, d, J=7.5 Hz), 6.89(2H, d, J=9.0Hz), 7.51-7.60(4H, m), 7.68-7.77(3H, m), 10.07(1H, s) (+)ESI-MS(m/z):455(M+H)⁺, 477(M+Na)⁺

[0674] Preparation 61

2-Chloro-N-{6-[4-(3-cyanobenzyl)-1-piperazinyl]-3-pyridinyl}-6-methylnicotinamide

[0675] The title compound was obtained in a similar manner as inPreparation 60 from3-{[4-(5-amino-2-pyridinyl)-1-piperazinyl]methyl}benzonitrile and2-chloro-6-methylnicotinic acid.

[0676]¹H-NMR(DMSO-d₆): δ 2.45(3H, s), 2.48-2.51(4H, m), 3.43-3.48(4H,m), 3.59(2H, s), 6.85(1H, d, J=9.1 Hz), 7.40(1H, d, J=7.8 Hz),7.53-7.60(1H, m), 7.69-7.90(5H, m), 8.38(1H, d, J=2.6 Hz), 10.40(1H, s)(+)ESI-MS(m/z): 447 (M+H)⁺, 469 (M+Na)⁺

EXAMPLE 68

[0677]N-{6-[4-(3-Cyanobenzyl)-1-piperazinyl]-3-pyridinyl}-6-methyl-2-(4-methyl-1-piperidinyl)nicotinamide

[0678] The title compound was obtained in a similar manner as in Example66 from2-chloro-N-{6-[4-(3-cyanobenzyl)-1-piperazinyl]-3-pyridinyl}-6-methylnicotinamideand 4-methylpiperidine.

[0679]¹H-NMR(DMSO-d₆): δ 0.89(3H, d, J=6.2 Hz), 1.14-1.21(2H, m),1.26-1.66(3H, m), 2.39(3H, s), 2.45-2.51(4H, m), 2.75-2.86(2H, m),3.43-3.58(4H, m), 3.58-3.69(4H, m), 6.79-6.87(2H, m), 7.53-7.60(1H, m),7.69-7.78(4H, m), 7.87-7.93(1H, m), 8.42(1H, d, J=2.6 Hz), 10.36(1H, s)(+)ESI-MS(m/z): 510(M+H)⁺, 532(M+Na)⁺

EXAMPLE 69N-{6-[4-(3-Cyanobenzyl)-1-piperazinyl]-3-pyridinyl}-2-(dimethylamino)-6-methylnicotinamide

[0680] The title compound was obtained in a similar manner as in Example67 from2-chloro-N-{6-[4-(3-cyanobenzyl)-1-piperazinyl]-3-pyridinyl}-6-methylnicotinamideand dimethylamine.

[0681]¹H-NMR(DMSO-d₆): δ 2.35(3H, s), 2.45-2.51(4H, m), 3.34(6H, s),3.42-3.46(4H, m), 3.58(2H, s), 6.61(1H, d, J=7.6 Hz), 6.83(2H, d, J=9.1Hz), 7.53-7.60(2H, m), 7.68-7.88(4H, m), 8.39-8.40(1H, m), 10.12(1H, s)(+)ESI-MS(m/z): 456(M+H)⁺, 478(M+Na)⁺

EXAMPLE 70

[0682] 1-[3-(Dimethylamino)propyl]-3-ethylcarbodiimide (10.0 g) wasadded to a solution ofN-(4-aminophenyl)-N-[2-(2-pyridinyl)ethyl]formamide (13.0 g),2-(dimethylamino)-4-methylbenzoic acid (11.6 g), 1-hydroxybenzotriazole(8.7 g) and 4-dimethylaminopyridine (0.33 g) in N,N-dimethylformamide(130 ml) under ice-cooling and the mixture was stirred at ambienttemperature for 18 hours.

[0683] The reaction mixture was poured into a mixture of ethyl acetateand water. The separated organic layer was washed with water, dried overmagnesium sulfate and evaporated in vacuo. The residue was purified bycolumn chromatography on silica gel using ethyl acetate as an eluent.The eluted fractions containing the desired product were collected andevaporated in vacuo to give2-(dimethylamino)-N-(4-{formyl[2-(2-pyridinyl)ethyl]amino}phenyl)-4-methylbenzamide(20.18 g).

[0684]¹H-NMR(DMSO-d₆): δ 2.35(3H, s), 2.77(6H, s), 2.91(2H, t, J=7.5Hz), 4.11(2H, t, J=7.5 Hz), 6.95(1H, d, J=7.9 Hz), 7.10(1H, s),7.17-7.33(4H, m), 7.62-7.82(4H, m), 8.34(1H, s), 8.45-8.52(1H, m), 11.55(1H, s)

EXAMPLE 71

[0685] conc. Hydrochloric acid (24.8 g) was added to a solution of2-(dimethylamino)-N-(4-{formyl[2-(2-pyridinyl)ethyl]amino}phenyl)-4-methylbenzamide(20.0 g) in methanol (100 ml) under ice-cooling and the mixture wasstirred at ambient temperature for 30 hours. The reaction mixture wasevaporated in vacuo and to the residue was added a mixture of ethylacetate and water. The mixture was adjusted to pH 9 with 20% aqueouspotassium carbonate solution. The separated organic layer was washedwith water, dried over magnesium sulfate and evaporated in vacuo. Theresidue was crystallized from a mixture of ethanol and heptane to give2-(dimethylamino)-4-methyl-N-(4-{[2-(2-pyridinyl)ethyl]amino}phenyl)benzamide(9.33 g).

[0686]¹H-NMR(DMSO-d₆): δ 2.33(3H, s), 2.75(6H, s), 2.99(2H, t, J=7.2Hz), 3.30-3.44(2H, m), 5.56(1H, t, J=5.7 Hz), 6.59(2H, d, J=8.8 Hz),6.94(1H, d, J=8.0 Hz), 7.08(1H, s), 7.18-7.27(1H, m), 7.32(1H, d, J=7.8Hz), 7.43(2H, d, J=8.8 Hz), 7.64-7.77(2H, m), 8.49-8.55(1H, m),11.18(1H, s) (+)ESI-MS(m/z): 375(M+H)⁺, 397(M+Na)⁺

[0687] Preparation 62

[0688] A mixture of methyl 4-chloro-2-aminobenzoate (5.4 g) and dimethylsulfate (7.5 ml) was stirred for 70 hours at 100° C. To the mixture wasadded a saturated aqueous sodium hydrogencarbonate solution and themixture was extracted with ethyl acetate. The extract layer was washedwith water, dried over magnesium sulfate and evaporated in vacuo. Theresidue was purified by column chromatography on silica gel using amixture of hexane and ethyl acetate (19:1 v/v) as an eluent. The elutedfractions containing the desired product were collected and evaporatedin vacuo to give methyl 4-chloro-2-(dimethylamino)benzoate (5.31 g).

[0689]¹H-NMR(DMSO-d₆): δ 2.79(6H, s), 3.81(3H, s), 6.82(1H, dd, J=1.9Hz, 8.3 Hz), 6.95(1H, d, J=1.9 Hz), 7.51(1H, d, J=8.3 Hz)(+)ESI-MS(m/z): 214(M+H)⁺, 236(M+Na)⁺

[0690] Preparation 63

[0691] A mixture of methyl4-chloro-2-{[(trifluoromethyl)sulfonyl]oxy}benzoate (5.0 g) and 2 mol/ltetrahydrofuran solution of dimethylamine (19.6 ml) was heated at 70° C.in sealed tube for 60 hours. To the reaction mixture was added a mixtureof ethyl acetate and water. The separated organic layer was washed withwater, dried over magnesium sulfate and evaporated in vacuo. The residuewas purified by column chromatography on silica gel using a mixture ofhexane and ethyl acetate (9:1 v/v) as an eluent. The eluted fractionscontaining the desired product were collected and evaporated in vacuo togive methyl 4-chloro-2-(dimethylamino)benzoate (2.24 g).

[0692]¹H-NMR(DMSO-d₆): δ 2.79(6H, s), 3.81(3H, s), 6.82(1H, dd, J=1.9Hz, 8.3 Hz), 6.95(1H, d, J=1.9 Hz), 7.51(1H, d, J=8.3 Hz)(+)ESI-MS(m/z): 214(M+H)⁺, 236(M+Na)⁺

[0693] Preparation 64

[0694] A mixture of methyl 4-chloro-2-(dimethylamino)benzoate (5.3 g)and sodium hydroxide (2.0 g) in a mixture of methanol (53 ml) and water(10 ml) was stirred under reflux for 20 hours. To the reaction mixturewas added conc. hydrochloric acid (4.1 ml) and the mixture wasevaporated in vacuo. The residue was purified by column chromatographyon silica gel using a mixture of chloroform and methanol (19:1 v/v) asan eluent. The eluted fractions containing the desired product werecollected and evaporated in vacuo to give4-chloro-2-(dimethylamino)benzoic acid (4.27 g).

[0695]¹H-NMR(DMSO-d₆): δ 2.82(6H, s), 7.18(1H, dd, J=2.0 Hz, 8.4 Hz),7.49(1H, d, J=2.0 Hz), 7.79(1H, d, J=8.4 Hz), 15.48(1H, s)(−)ESI-MS(m/z): 397(M−H)⁻

EXAMPLE 72

[0696] The following compound was obtained in substantially the samemanner as in Example 70.

4-Chloro-2-(dimethylamino)-N-(4-{formyl[2-(2-pyridinyl)ethyl]amino}phenyl)benzamide

[0697]¹H-NMR(DMSO-d₆): δ 2.82(6H, s), 2.91(2H, t, J=7.5 Hz), 4.11(2H, t,J=7.5 Hz), 7.02(1H, dd, J=2.0 Hz, 8.2 Hz), 7.10(1H, d, J=2.0 Hz),7.19-7.32(4H, m), 7.52(1H, d, J=8.2 Hz), 7.66-7.73(1H, m), 7.76(2H, d,J=8.8 Hz), 8.34(1H, s), 8.47-8.50(1H, m), 10.80(1H, s)

EXAMPLE 73

[0698] The following compound was obtained in substantially the samemanner as in Example 71.

4-Chloro-2-(dimethylamino)-N-(4-{[2-(2-pyridinyl)ethyl]amino}phenyl)benzamide

[0699]¹H-NMR(DMSO-d₆): δ 2.79(6H, s), 2.98(2H, t, J=7.2 Hz),3.29-3.44(2H, m), 5.57(1H, t, J=5.8 Hz), 6.58(2H, d, J=8.7 Hz), 7.01(1H,dd, J=1.9 Hz, 8.1 Hz), 7.08(1H, d, J=1.9 Hz), 7.18-7.27(1H, m), 7.32(1H,d, J=7.7 Hz), 7.41(2H, d, J=8.7 Hz), 7.52(1H, d, J=8.1 Hz),7.66-7.77(1H, m), 8.49-8.54(1H, m), 10.40(1H, s) (+)ESI-MS(m/z):395(M+H)⁺, 417(M+Na)⁺

EXAMPLE 74

[0700] 1-[3-(Dimethylamino)propyl]-3-ethylcarbodiimide (0.19 g) wasadded to a solution of tert-butyl4-aminophenyl[2-(2-pyridinyl)ethyl]carbamate (0.31 g),4-chloro-2-(dimethylamino)benzoic acid (0.24 g), 1-hydroxybenzotriazole(0.16 g) and 4-dimethylaminopyridine (6 mg) in tetrahydrofuran (4 ml)and the mixture was stirred at ambient temperature for 18 hours. To thereaction mixture was added a solution of 4N hydrogen chloride in1,4-dioxane (7.5 ml) and the mixture was stirred at ambient temperaturefor 30 hours. The reaction mixture was poured into a mixture of ethylacetate and water, and the mixture was adjusted to pH 9 with potassiumcarbonate. The separated organic layer was washed with water, dried overmagnesium sulfate and evaporated in vacuo. The residue was crystallizedfrom ethyl acetate to give4-chloro-2-(dimethylamino)-N-(4-{[2-(2-pyridinyl)ethyl]amino}phenyl)benzamide(0.33 g).

[0701]¹H-NMR(DMSO-d₆): δ 2.79(6H, s), 2.98(2H, t, J=7.2 Hz),3.29-3.44(2H, m), 5.57(1H, t, J=5.8 Hz), 6.58(2H, d, J=8.7 Hz), 7.01(1H,dd, J=1.9 Hz, 8.1 Hz), 7.08(1H, d, J=1.9 Hz), 7.18-7.27(1H, m), 7.32(1H,d, J=7.7 Hz), 7.41(2H, d, J=8.7 Hz), 7.52(1H, d, J=8.1 Hz),7.66-7.77(1H, m), 8.49-8.54(1H, m), 10.40(1H, s) (+)ESI-MS(m/z):395(M+H)⁺, 417(M+Na)⁺

[0702] Preparation 65

[0703] The following compound was obtained in substantially the samemanner as in Preparation 62.

Methyl 2-(dimethylamino)-4-fluorobenzoate

[0704]¹H-NMR(DMSO-d₆): δ 2.79(6H, s), 3.80(3H, s), 6.54-6.65(1H, m),6.73(1H, dd, J=2.4 Hz, 12.7 Hz), 7.57(1H, dd, J=7.2 Hz, 8.5 Hz)

[0705] Preparation 66

[0706] The following compound was obtained in substantially the samemanner as in Preparation 64.

2-(Dimethylamino)-4-fluorobenzoic acid

[0707]¹H-NMR(DMSO-d₆): δ 2.89(6H, s), 6.99-7.11(1H, m), 7.41(1H, dd,J=2.5 Hz, 11.2 Hz), 7.91(1H, dd, J=6.8 Hz, 8.7 Hz), 10.43-13.22(1H,br-s) (−)ESI-MS(m/z): 182(M−H)⁻

EXAMPLE 75

[0708] The following compound was obtained in substantially the samemanner as in Example 74.

2-(Dimethylamino)-4-fluoro-N-(4-{[2-(2-pyridinyl)ethyl]amino}phenyl)benzamide

[0709]¹H-NMR(DMSO-d₆): δ 2.79(6H, s), 2.99(2H, t, J=7.2 Hz),3.31-3.43(2H, m), 5.58(1H, s), 6.59(2H, d, J=8.8 Hz), 6.73-6.84(1H, m),6.89(1H, dd, J=2.4 Hz, 12.1 Hz), 7.18-7.27(1H, m), 7.32(1H, d, J=7.7Hz), 7.42(2H, d, J=8.8 Hz), 7.57(1H, dd, J=7.2 Hz, 8.4 Hz),7.67-7.76(1H, m), 8.50-8.56(1H, m), 10.38(1H, s) (+) ESI-MS (m/z): 379(M+H)⁺, 401 (M+Na)⁺

[0710] Preparation 67

[0711] A mixture of 2-fluoro-4-(trifluoromethyl)benzonitrile (5.0 g) and2 mol/l tetrahydrofuran solution of dimethylamine (39.7 ml) was heatedat 80° C. in sealed tube for 15 hours. To the reaction mixture was addeda mixture of ethyl acetate and water. The separated organic layer waswashed with water, dried over magnesium sulfate and evaporated in vacuoto give 2-(dimethylamino)-4-(trifluoromethyl)benzonitrile (5.55 g).

[0712]¹H-NMR(DMSO-d₆): δ 3.09(6H, s), 7.15(1H, d, J=8.0 Hz), 7.21(1H,s), 7.82(1H, d, J=8.0 Hz)

[0713] Preparation 68

[0714] A mixture of 2-(dimethylamino)-4-(trifluoromethyl)benzonitrile(5.0 g) and sodium hydroxide (2.1 g) in ethylene glycol (22 ml) wasstirred at 180° C. for 6 hours. The reaction mixture was added to water(22 ml) at 80° C. and the mixture was stirred at the same temperaturefor an hour. To the mixture was added a saturated aqueous sodiumchloride solution and adjusted to pH 4 with 6N hydrochloric acid. Themixture was extracted with a mixture of ethyl acetate andtetrahydrofuran. The organic layer was dried over magnesium sulfate andevaporated in vacuo. The residue was triturated with diisopropyl etherto give 2-(dimethylamino)-4-(trifluoromethyl)benzoic acid (4.51 g).

[0715]¹H-NMR(DMSO-d₆): δ 2.88(6H, s), 7.35(1H, dd, J=0.9 Hz, 8.0 Hz),7.56(1H, d, J=0.9 Hz), 7.87(1H, d, J=8.0 Hz), 15.03(1H, s)(−)ESI-MS(m/z): 232(M−H)⁻

EXAMPLE 76

[0716] The following compound was obtained in substantially the samemanner as in Example 74.

2-(Dimethylamino)-N-(4-{[2-(2-pyridinyl)ethyl]amino}phenyl)-4-(trifluoromethyl)benzamide

[0717]¹H-NMR(DMSO-d₆): δ 2.86(6H, s), 2.99(2H, t, J=7.2 Hz),3.29-3.45(2H, m), 5.59(1H, t, J=5.7 Hz), 6.59(2H, d, J=8.8 Hz),7.17-7.28(3H, m), 7.32(1H, d, J=7.8 Hz), 7.43(2H, d, J=8.8 Hz), 7.62(1H,d, J=8.1 Hz), 7.66-7.77(1H, m), 8.48-8.56(1H, m), 10.28(1H, s)(+)ESI-MS(m/z): 429(M+H)⁺, 451(M+Na)⁺

[0718] Preparation 69

[0719] The following compound was obtained in substantially the samemanner as in Preparation 63.

Benzyl 2-(dimethylamino)-4-methoxybenzoate

[0720]¹H-NMR(DMSO-d₆): δ 2.74(6H, s), 3.78(3H, s), 5.26(2H, s),6.39-6.46(2H, m), 7.32-7.49(5H, m), 7.57-7.64(1H, m)

[0721] Preparation 70

[0722] To a mixture of benzyl 2-(dimethylamino)-4-methoxybenzoate (19.2g) in methanol (200 ml) was added 10% palladium on carbon (6.0 g, 50%wet). The reaction mixture was stirred at ambient temperature for 3hours under hydrogen atmosphere.

[0723] The catalyst was filtered off and the solvent was removed byconcentration. The residue was triturated with diisopropyl ether to give2-(dimethylamino)-4-methoxybenzoic acid (11.46 g).

[0724]¹H-NMR(DMSO-d₆): δ 2.78(6H, s), 3.84(3H, s), 6.91(1H, dd, J=2.4Hz, 8.8 Hz), 7.20(1H, d, J=2.4 Hz), 7.90(1H, d, J=8.8 Hz), 17.20(1H, s)(−)ESI-MS(m/z): 194(M−H)⁻

EXAMPLE 77

[0725] The following compound was obtained in substantially the samemanner as in Example 74.

2-(Dimethylamino)-4-methoxy-N-(4-{[2-(2-pyridinyl)ethyl]amino}phenyl)benzamide

[0726]¹H-NMR(DMSO-d₆): δ 2.75(6H, s), 2.99(2H, t, J=7.2 Hz),3.30-3.45(2H, m), 3.81(3H, s), 5.57(1H, t, J=5.7 Hz), 6.59(2H, d, J=8.8Hz), 6.67-6.78(2H, m), 7.18-7.27(1H, m), 7.32(1H, d, J=7.8 Hz), 7.43(2H,d, J=8.8 Hz), 7.66-7.79(2H, m), 8.50-8.55(1H, m), 11.08(1H, s)(+)ESI-MS(m/z): 391(M+H)⁺

[0727] Preparation 71

[0728] To a mixture of 4-acetyl-2-nitrophenol (23.0 g) and 37% aqueousformaldehyde (190 ml) in methanol (460 ml) was added 10% palladium oncarbon (11.5 g, 50% wet). The reaction mixture was stirred at ambienttemperature for 16 hours under hydrogen atmosphere. The catalyst wasfiltered off and the solvent was removed by concentration. To theresidue was added ethyl acetate and the mixture was washed with brine,dried over magnesium sulfate and evaporated in vacuo. The residue wastriturated with diisopropyl ether to give1-[3-(dimethylamino)-4-hydroxyphenyl]ethanone (15.37 g).

[0729]¹H-NMR(DMSO-d₆):δ 2.47(3H, s), 2.70(6H, s), 6.84(1H, d, J=8.2 Hz),7.40(1H, d, J=2.0 Hz), 7.50(1H, dd, J=2.0 Hz, 8.2 Hz), 10.10(1H, s)(+)ESI-MS(m/z): 180(M+H)⁺, 202(M+Na)⁺

[0730] Preparation 72

[0731] Trifluoromethanesulfonic anhydride (25.6 ml) was added dropwiseto a mixture of 1-[3-(dimethylamino)-4-hydroxyphenyl]ethanone (22.7 g)and triethylamine (21.2 ml) in dichloromethane (227 ml) underice-cooling and the mixture was stirred at the same temperature for 1.5hours. The reaction mixture was poured into a saturated aqueous sodiumhydrogencarbonate solution. The separated organic layer was washed withwater, dried over magnesium sulfate and evaporated in vacuo to give4-acetyl-2-(dimethylamino)phenyl trifluoromethanesulfonate (49.27 g) asa crude oil.

[0732]¹H-NMR(DMSO-d₆):δ 2.62(3H, s), 2.78(6H, s), 7.47-7.54(1H, m),7.66-7.73(2H, m)

[0733] Preparation 73

[0734] A mixture of 4-acetyl-2-(dimethylamino)phenyltrifluoromethanesulfonate (39.4 g), palladium (II) acetate (1.4 g),1,3-bis(diphenylphosphino)propane (2.6 g) and triethylamine (52.9 ml) ina mixture of dimethyl sulfoxide (200 ml) and methanol (100 ml) waspurged with carbon monoxide for 30 minutes at ambient temperature andthe mixture was stirred under a carbon monoxide balloon at 70° C. for 5hours. The reaction mixture was diluted with water and extracted withethyl acetate. The organic layer was washed with water, dried overmagnesium sulfate and evaporated in vacuo. The residue was purified bycolumn chromatography on silica gel using a mixture of hexane and ethylacetate (4:1 v/v) as an eluent. The eluted fractions containing thedesired product were collected and evaporated in vacuo to give methyl4-acetyl-2-(dimethylamino)benzoate (14.36 g).

[0735]¹H-NMR(DMSO-d₆):δ 2.59(3H, s), 2.82(6H, s), 3.84(3H, s), 7.37(1H,dd, J=1.5 Hz, 7.9 Hz), 7.42(1H, d, J=1.5 Hz), 7.59(1H, d, J=7.9 Hz)

[0736] Preparation 74

[0737] Sodium borohydride (0.56 g) was added to a mixture of methyl4-acetyl-2-(dimethylamino)benzoate (6.5 g) in methanol (65 ml) underice-cooling and the mixture was stirred for 30 minutes at the sametemperature. The solvent was removed by concentration. To the residuewas added ethyl acetate and the mixture was washed with water, driedover magnesium sulfate and evaporated in vacuo to give methyl2-(dimethylamino)-4-(1-hydroxyethyl)benzoate (6.5 g).

[0738]¹H-NMR(DMSO-d₆):δ 1.31(3H, d, J=6.5 Hz), 2.76(6H, s), 3.78(3H, s),4.61-4.76(1H, m), 5.19(1H, d, J=4.3 Hz), 4.79(1H, dd, J=1.2 Hz, 7.9 Hz),6.96(1H, d, J=1.2 Hz), 7.46(1H, d, J=7.9 Hz)

[0739] Preparation 75

[0740] To a mixture of methyl2-(dimethylamino)-4-(1-hydroxyethyl)benzoate (6.4 g) and 4N hydrogenchloride in 1,4-dioxane (21.5 ml) in methanol (64 ml) was added 10%palladium on carbon (2.0 g, 50% wet). The reaction mixture was stirredat 35° C. for 16 hours under hydrogen atmosphere. The catalyst wasfiltered off and the solvent was removed by concentration. To theresidue was added ethyl acetate and adjusted to pH 9 with potassiumcarbonate. The separated organic layer was washed with water, dried overmagnesium sulfate and evaporated in vacuo to give methyl2-(dimethylamino)-4-ethylbenzoate (5.47 g).

[0741]¹H-NMR(DMSO-d₆):δ 1.17(3H, t, J=7.6 Hz), 2.58(2H, q, J=7.6 Hz),2.75(6H, s), 3.78(3H, s), 6.68(1H, d, J=7.9 Hz), 6.79(1H, s), 7.45(1H,d, J=7.9 Hz)

[0742] Preparation 76

[0743] The following compound was obtained in substantially the samemanner as in Preparation 64.

[0744] 2-(Dimethylamino)-4-ethylbenzoic acid

[0745]¹H-NMR(DMSO-d₆):δ 1.21(3H, t, J=7.6 Hz), 2.68(2H, q, J=7.6 Hz),2.81(6H, s), 7.22(1H, d, J=7.9 Hz), 7.57(1H, s), 7.89(1H, d, J=7.9 Hz),17.79(1H, s)

[0746] (+)ESI-MS(m/z): 194(M+H)⁺, 216(M+Na)⁺

EXAMPLE 78

[0747] The following compound was obtained in substantially the samemanner as in Example 74.

[0748]2-(Dimethylamino)-4-ethyl-N-(4-{[2-(2-pyridinyl)ethyl]amino}phenyl)benzamide

[0749]¹H-NMR(DMSO-d₆):δ 1.20(3H, t, J=7.5 Hz), 2.63(2H, q, J=7.5 Hz),2.76(6H, s), 2.99(2H, t, J=7.2 Hz), 3.30-3.43(2H, m), 5.57(1H, t, J=5.7Hz), 6.60(2H, d, J=8.7 Hz), 6.97(1H, d, J=7.9 Hz), 7.08(1H, s), 7.22(1H,dd, J=5.4 Hz, 7.2 Hz), 7.32(1H, d, J=7.9 Hz), 7.44(2H, d, J=8.7 Hz),7.64-7.76(2H, m), 8.49-8.56(1H, m), 11.13(1H, s)

[0750] (+)ESI-MS(m/z): 389(M+H)⁺, 411(M+Na)⁺

[0751] Preparation 77

[0752] Methyl 4-acetyl-2-(dimethylamino)benzoate (5.0 g) was added to amixture of methyltriphenylphosphonium bromide (12.1 g) and potassiumtert-butoxide (3.55 g) in tetrahydrofuran (120 ml) at ambienttemperature and the mixture was stirred for 3 hours at 57° C. Thereaction mixture was poured into a mixture of ethyl acetate and waterand adjusted to pH 2 with 6N hydrochloric acid. The separated organiclayer was washed with water, dried over magnesium sulfate and evaporatedin vacuo. The residue was purified by column chromatography on silicagel using a mixture of hexane and ethyl acetate (9:1 v/v) as an eluent.The eluted fractions containing the desired product were collected andevaporated in vacuo to give methyl2-(dimethylamino)-4-isopropenylbenzoate (4.83 g).

[0753]¹H-NMR(DMSO-d₆):δ 2.11(3H, s), 2.78(6H, s), 3.80(3H, s),5.14-5.18(1H, m), 5.45-5.48(1H, m), 6.95(1H, dd, J=1.7 Hz, 8.0 Hz),6.99(1H, d, J=1.7 Hz), 7.50(1H, d, J=8.0 Hz)

[0754] Preparation 78

[0755] To a mixture of methyl 2-(dimethylamino)-4-isopropenylbenzoate(4.8 g) in methanol (50 ml) was added 10% palladium on carbon (1.0 g,50% wet). The reaction mixture was stirred at ambient temperature for 6hours under hydrogen atmosphere. The catalyst was filtered off and thesolvent was removed by concentration to give methyl2-(dimethylamino)-4-isopropylbenzoate (4.56 g).

[0756]¹H-NMR(DMSO-d₆):δ 1.19(6H, d, J=6.8 Hz), 2.73 -2.97(1H, m),2.76(6H, s), 3.78(3H, s), 6.71(1H, dd, J=1.4 Hz, 7.9 Hz), 6.80(1H, d,J=1.4 Hz), 7.45(1H, d, J=7.9 Hz)

[0757] Preparation 79

[0758] The following compound was obtained in substantially the samemanner as in Preparation 64.

[0759] 2-(Dimethylamino)-4-isopropylbenzoic acid

[0760]¹H-NMR(DMSO-d₆):δ 1.23(6H, d, J=7.0 Hz), 2.82(6H, s),2.88-3.06(1H, m), 7.27(1H, d, J=8.0 Hz), 7.61(1H, s), 7.92(1H, d, J=8.0Hz), 17.82(1H, s)

[0761] (−)ESI-MS(m/z): 206(M−H)⁻

EXAMPLE 79

[0762] The following compound was obtained in substantially the samemanner as in Example 74.

[0763]2-(Dimethylamino)-4-isopropyl-N-(4-([2-(2-pyridinyl)ethyl]amino}phenyl)benzamide

[0764]¹H-NMR(DMSO-d₆):δ 1.22(6H, d, J=6.7 Hz), 2.76(6H, s),2.82-3.00(1H, m), 2.99(2H, t, J=7.3 Hz), 3.30-3.44(2H, m), 5.57(1H, t,J=5.8 Hz), 6.59(2H, d, J=8.8 Hz), 6.99(1H, dd, J=1.3 Hz, 8.0 Hz),7.09(1H, d, J=1.3 Hz), 7.18-7.27(1H, m), 7.32(1H, d, J=7.8 Hz), 7.44(2H,d, J=8.8 Hz), 7.63-7.77(2H, m), 8.50-8.55(1H, m), 11.06(1H, s)

EXAMPLE 80

[0765] 4N Hydrogen chloride in ethyl acetate (0.85 ml) was added to amixture of2-(dimethylamino)-4-isopropyl-N-(4-{[2-(2-pyridinyl)ethyl]amino}phenyl)benzamide(0.34 g) in ethyl acetate (20 ml) and the mixture was stirred at ambienttemperature for an hour. The isolated precipitate was collected byfiltration to give2-(dimethylamino)-4-isopropyl-N-(4-([2-(2-pyridinyl)ethyl]amino}phenyl)benzamidetrihydrochloride (0.35 g).

[0766]¹H-NMR(DMSO-d₆):δ 1.27(6H, d, J=6.9 Hz), 2.97-3.14(1H, m),3.25(6H, s), 3.54(2H, t, J=6.6 Hz), 3.74(2H, t, J=6.6 Hz), 7.30(2H, d,J=8.7 Hz), 7.51(1H, d, J=8.0 Hz), 7.78(2H, d, J=8.7 Hz), 7.88-7.98(2H,m), 8.04(1H, d, J=8.0 Hz), 8.14(1H, d, J=8.0 Hz), 8.47-8.57(1H, m),8.78-8.86(1H, m), 11.19(1H, s) (+)ESI-MS(m/z): 403(M+H)⁺, 425(M+Na)⁺

[0767] Preparation 80

[0768] The following compound was obtained in substantially the samemanner as in Preparation 71.

[0769] 4-tert-Butyl-2-(dimethylamino)phenol

[0770]¹H-NMR(DMSO-d₆):δ 1.23(9H, s), 2.66(6H, s), 6.65(1H, d, J=8.1 Hz),6.77(1H, dd, J=2.2 Hz, 8.1 Hz), 6.85(1H, d, J=2.2 Hz), 8.74(1H, s)

[0771] Preparation 81

[0772] The following compound was obtained in substantially the samemanner as in Preparation 72.

[0773] 4-tert-Butyl-2-(dimethylamino)phenyl trifluoromethanesulfonate

[0774]¹H-NMR(DMSO-d₆):δ 1.29(9H, s), 2.73(6H, s), 7.07-7.16(1H, m),7.17-7.26(2H, m)

[0775] Preparation 82

[0776] The following compound was obtained in substantially the samemanner as in Preparation 73.

[0777] Methyl 4-tert-butyl-2-(dimethylamino)benzoate

[0778]¹H-NMR(DMSO-d₆):δ 1.27(9H, s), 2.77(6H, s), 3.78(3H, s), 6.65(1H,d, J=8.1 Hz), 6.85(1H, s), 7.46(1H, d, J=8.1 Hz)

[0779] Preparation 83

[0780] The following compound was obtained in substantially the samemanner as in Preparation 64.

[0781] 4-tert-Butyl-2-(dimethylamino)benzoic acid

[0782]¹H-NMR(DMSO-d₆):δ 1.32(9H, s), 2.84(6H, s), 7.43(1H, dd, J=1.8 Hz,8.3 Hz), 7.73(1H, d, J=1.8 Hz), 7.93(1H, d, J=8.3 Hz), 17.99(1H, s)

[0783] (−)ESI-MS(m/z): 220(M−H)⁻

EXAMPLE 81

[0784] The following compound was obtained in substantially the samemanner as in Example 74.

[0785]4-tert-Butyl-2-(dimethylamino)-N-(4-{[2-(2-pyridinyl)ethyl]amino}phenyl)benzamide

[0786]¹H-NMR(DMSO-d₆):δ 1.30(9H, s), 2.77(6H, s), 2.99(2H, t, J=7.4 Hz),3.37(2H, t, J=7.4 Hz), 5.67(1H, s), 6.59(2H, d, J=8.8 Hz), 7.14(1H, dd,J=1.8 Hz, 8.1 Hz), 7.18-7.27(2H, m), 7.32(1H, d, J=7.7 Hz), 7.44(2H, d,J=8.8 Hz), 7.64-7.77(2H, m), 8.50-8.55(1H, m), 11.11 (1H, s)

EXAMPLE 82

[0787] The following compound was obtained in substantially the samemanner as in Example 80.

[0788]4-tert-Butyl-2-(dimethylamino)-N-(4-{[2-(2-pyridinyl)ethyl]amino}phenyl)benzamidetrihydrochloride

[0789]¹H-NMR(DMSO-d₆):δ 1.36(9H, s), 3.27(6H, s), 3.53(2H, t, J=6.5 Hz),3.73(2H, t, J=6.5 Hz), 7.25(2H, d, J=8.7 Hz), 7.63(1H, d, J=8.3 Hz),7.76(2H, d, J=8.7 Hz), 7.87-7.97(1H, m), 7.99-8.08(2H, m), 8.15(1H, d,J=8.3 Hz), 8.45-8.56(1H, m), 8.78-8.85(1H, m), 11.18(1H, s)(+)ESI-MS(m/z): 417(M+H)⁺, 439(M+Na)⁺

EXAMPLE 83

[0790] The following compound was obtained in substantially the samemanner as in Example 74.

[0791]2-(Diethylamino)-4-methyl-N-(4-{[2-(2-pyridinyl)ethyl]amino}phenyl)benzamide

[0792]¹H-NMR(DMSO-d₆):δ 0.97(6H, t, J=7.1 Hz), 2.36(3H, s),2.94-3.17(6H, m), 3.30-3.45(2H, m), 2.28(1H, t, J=5.7 Hz), 6.62(2H, d,J=8.8 Hz), 7.13(1H, d, J=8.0 Hz), 7.18-7.30(2H, m), 7.32(1H, d, J=7.8Hz), 7.45(2H, d, J=8.8 Hz), 7.66-7.76(1H, m), 8.01(1H, d, J=8.0 Hz),8.49-8.55(1H, m), 12.80(1H, s) (+)ESI-MS(m/z): 403(M+H)⁺, 425(M+Na)⁺

[0793] Preparation 84

[0794] A mixture of benzyl4-methoxy-2-{[(trifluoromethyl)sulfonyl]oxy}benzoate (34.0 g) and4-methylpiperidine (30.9 ml) in acetonitrile (100 ml) was stirred underreflux for 30 hours. The solvent was removed by concentration. Theresidue was purified by column chromatography on silica gel using amixture of hexane and ethyl acetate (9:1 v/v) as an eluent. The elutedfractions containing the desired product were collected and evaporatedin vacuo to give benzyl 4-methoxy-2-(4-methyl-1-piperidinyl)benzoate(22.88 g).

[0795]¹H-NMR(DMSO-d₆):δ 0.87(3H, d, J=6.1 Hz), 1.06-1.29(2H, m),1.29-1.48(1H, m), 1.48-1.63(2H, m), 2.53-2.71(2H, m), 3.12-3.25(2H, m),3.78(3H, s), 5.26(2H, s), 6.48-6.57(2H, m), 7.29-7.49(5H, m), 7.68(1H,d, J=8.3 Hz)

[0796] Preparation 85

[0797] The following compound was obtained in substantially the samemanner as in Preparation 70.

[0798] 4-Methoxy-2-(4-methyl-1-piperidinyl)benzoic acid

[0799]¹H-NMR(DMSO-d₆):δ 1.99(3H, d, J=6.4 Hz), 1.20-1.43(2H, m),1.55-1.78(1H, m), 1.78-1.93(2H, m), 2.93-3.17(4H, m), 3.85(3H, s),6.99(1H, dd, J=2.5 Hz, 8.8 Hz), 7.26(1H, d, J=2.5 Hz), 7.98(1H, d, J=8.8Hz), 17.63(1H, s) (−)ESI-MS(m/z): 248(M−H)⁻

EXAMPLE 84

[0800] The following compound was obtained in substantially the samemanner as in Example 74.

[0801]4-Methoxy-2-(4-methyl-1-piperidinyl)-N-(4-{[2-(2-pyridinyl)ethyl]amino}phenyl)benzamide

[0802]¹H-NMR(DMSO-d₆):δ 0.97(3H, d, J=6.0 Hz), 1.23-1.65(3H, m),1.68-1.83(2H, m), 2.70-2.86(2H, m), 2.99(2H, t, J=7.1 Hz), 3.04-3.16(2H,m), 3.30-3.43(2H, m), 3.81(3H, s), 5.58(1H, t, J=5.7 Hz), 6.61(2H, d,J=8.8 Hz), 6.77-6.87(2H, m), 7.18-7.27(1H, m), 7.33(1H, d, J=7.7 Hz),7.47(2H, d, J=8.8 Hz), 7.66-7.76(1H, m), 7.90(1H, d, J=8.4 Hz),8.49-8.55(1H, m), 11.58(1H, s) (+)ESI-MS(m/z): 445(M+H)⁺

[0803] Preparation 86

[0804] The following compound was obtained in substantially the samemanner as in Preparation 62.

[0805] Methyl 2-(dimethylamino)-3-methylbenzoate

[0806]¹H-NMR(DMSO-d₆):δ 2.27(3H, s), 2.69(6H, s), 3.84(3H, s), 7.02(1H,t, J=7.5 Hz), 7.23-7.36(2H, m) (+)ESI-MS(m/z): 194(M+H)⁺, 216(M+Na)⁺

[0807] Preparation 87

[0808] The following compound was obtained in substantially the samemanner as in Preparation 64.

[0809] 2-(Dimethylamino)-3-methylbenzoic acid

[0810]¹H-NMR(DMSO-d₆):δ 2.48(3H, s), 2.90(6H, s), 7.31(1H, t, J=7.6 Hz),7.45(1H, dd, J=1.5 Hz, 7.6 Hz), 7.89(1H, dd, J=1.5 Hz, 7.6 Hz),18.19(1H, s) (−)ESI-MS(m/z): 178(M−H)⁻

EXAMPLE 85

[0811] The following compound was obtained in substantially the samemanner as in Example 74.

[0812]2-(Dimethylamino)-3-methyl-N-(4-{[2-(2-pyridinyl)ethyl]amino}phenyl)benzamide

[0813]¹H-NMR(DMSO-d₆):δ 2.31(3H, s), 2.75(6H, s), 2.99(2H, t, J=7.2 Hz),3.29-3.45(2H, m), 5.55(1H, t, J=5.7 Hz), 6.58(2H, d, J=8.8 Hz), 7.06(1H,t, J=7.5 Hz), 7.18-7.37(4H, m), 7.45(2H, d, J=8.8 Hz), 7.71(1H, dt,J=1.8 Hz, 7.6 Hz), 8.47-8.55(1H, m), 10.45(1H, s) (+)ESI-MS(m/z):375(M+H)⁺, 397(M+Na)⁺

EXAMPLE 86

[0814] The following compound was obtained in substantially the samemanner as in Example 74.

[0815]2-(Dimethylamino)-5-methyl-N-(4-{[2-(2-pyridinyl)ethyl]amino}phenyl)benzamide

[0816]¹H-NMR(DMSO-d₆):δ 2.30(3H, s), 2.72(6H, s), 2.99(2H, t, J=7.2 Hz),3.31-3.44(2H, m), 5.58(1H, t, J=5.7 Hz), 6.60(2H, d, J=8.8 Hz),7.15-7.36(4H, m), 7.45(2H, d, J=8.8 Hz), 7.62(1H, d, J=1.8 Hz), 7.71(1H,dt, J=1.7 Hz, 7.6 Hz), 8.50-8.56(1H, m), 11.41(1H, s) (+)ESI-MS(m/z):375(M+H)⁺, 397(M+Na)⁺

[0817] Preparation 88

[0818] The following compound was obtained in substantially the samemanner as in Preparation 62.

[0819] Methyl 5-chloro-2-(dimethylamino)benzoate

[0820]¹H-NMR(DMSO-d₆):δ 2.77(6H, s), 3.82(3H, s), 6.98(1H, d, J=8.9 Hz),7.39(1H, dd, J=2.6 Hz, 8.9 Hz), 7.49(1H, d, J=2.6 Hz)

[0821] Preparation 89

[0822] The following compound was obtained in substantially the samemanner as in Preparation 64.

[0823] 5-Chloro-2-(dimethylamino)benzoic acid

[0824]¹H-NMR(DMSO-d₆):δ 2.82(6H, s), 7.49-7.66(2H, m), 7.76(1H, s),15.37-17.48(1H, br) (−)ESI-MS(m/z): 198(M−H)⁻

EXAMPLE 87

[0825] The following compound was obtained in substantially the samemanner as in Example 74.

[0826]5-Chloro-2-(dimethylamino)-N-(4-{[2-(2-pyridinyl)ethyl]amino}phenyl)benzamide

[0827]¹H-NMR(DMSO-d₆):δ 2.77(6H, s), 2.99(2H, t, J=7.2 Hz),3.31-3.44(2H, m), 5.61(1H, t, J=5.7 Hz), 6.60(2H, d, J=8.8 Hz), 7.16(1H,d, J=8.7 Hz), 7.18-7.27(1H, m), 7.32(1H, d, J=7.8 Hz), 7.39-7.48(3H, m),7.56(1H, d, J=2.7 Hz), 7.66-7.77(1H, m), 8.50-8.56(1H, m), 10.73(1H, s)

EXAMPLE 88

[0828] The following compound was obtained in substantially the samemanner as in Example 80.

[0829]5-Chloro-2-(dimethylamino)-N-(4-{[2-(2-pyridinyl)ethyl]amino}phenyl)benzamidetrihydrochloride

[0830]¹H-NMR(DMSO-d₆):δ 2.96(6H, s), 3.51(2H, t, J=6.9 Hz), 3.74(2H, t,J=6.9 Hz), 7.28(2H, d, J=8.7 Hz), 7.52(1H, d, J=8.8 Hz), 7.63(1H, dd,J=2.3 Hz, 8.8 Hz), 7.73(2H, d, J=8.8 Hz), 7.80(1H, d, J=2.3 Hz),7.86-7.96(1H, m), 8.02(1H, d, J=8.0 Hz), 8.45-8.55(1H, m), 8.78-8.85(1H,m), 11.07(1H, s)

EXAMPLE 89

[0831] 1-[3-(Dimethylamino)propyl]-3-ethylcarbodiimide (0.19 g) wasadded to a solution of 4-(2-pyridinylmethyl)aniline (0.18 g),2-(dimethylamino)-4-methylbenzoic acid (0.22 g), 1-hydroxybenzotriazole(0.16 g) and 4-dimethylaminopyridine (6 mg) in tetrahydrofuran (5 ml)and the mixture was stirred at ambient temperature for 18 hours. Thereaction mixture was poured into a mixture of ethyl acetate and water.The separated organic layer was washed with water, dried over magnesiumsulfate and evaporated in vacuo. The residue was purified by columnchromatography on silica gel using a mixture of ethyl acetate anddiisopropyl ether (2:3 v/v) as an eluent. The eluted fractionscontaining the desired product were collected and evaporated in vacuo togive 2-(dimethylamino)-4-methyl-N-[4-(2-pyridinylmethyl)phenyl]benzamide(0.14 g).

[0832]¹H-NMR(DMSO-d₆):δ 2.34(3H, s), 2.75(6H, s), 4.05(2H, s), 6.94(1H,d, J=8.2 Hz), 7.09(1H, s), 7.16-7.30(4H, m), 7.59-7.75(4H, m),8.46-8.52(1H, m), 11.46(1H, s) (+)ESI-MS(m/z): 346(M+H)⁺, 368(M+Na)⁺

EXAMPLE 90

[0833] The following compound was obtained in substantially the samemanner as in Example 89.

[0834]4-Methyl-2-(4-methyl-1-piperidinyl)-N-{4-[2-(2-pyridinyl)ethoxy]phenyl}benzamide

[0835]¹H-NMR(DMSO-d₆):δ 0.95(3H, d, J=6.1 Hz), 1.20-1.62(3H, m),1.66-1.82(2H, m), 2.34(3H, s), 2.68-2.88(2H, m), 3.02-3.23(4H, m),4.34(2H, t, J=6.6 Hz), 6.94(2H, d, J=8.9 Hz), 7.04(1H, d, J=8.0 Hz),7.16(1H, s), 7.20-7.29(1H, m), 7.37(1H, d, J=7.8 Hz), 7.60-7.85(4H, m),8.48-8.55(1H, m), 11.79(1H, s) (+)ESI-MS(m/z): 430(M+H)⁺, 452(M+Na)⁺

[0836] Preparation 90

[0837] A mixture of benzyl 2-chloro-6-methylnicotinate (8.15 g) and4-methylpiperidine (12.4 g) in tetrahydrofuran (50 ml) was stirred at75-80° C. for 2.5 hours.

[0838] The reaction mixture was poured into a mixture of ethyl acetateand water, and the organic layer was washed with brine and dried overmagnesium sulfate. The solvent was evaporated in vacuo and the residuewas chromatographed on silica gel eluting with ethyl acetate: n-hexane(2:8 v/v). The eluted fractions containing the desired product werecollected and evaporated in vacuo to give benzyl6-methyl-2-(4-methyl-1-piperidinyl)nicotinate (9.49 g).

[0839]¹H-NMR(DMSO-d₆):δ 0.86 (3H, d, J=6.0 Hz), 0.96-1.21 (2H, m),1.42-1.57 (3H, m), 2.34 (3H, s), 2.72-2.83 (2H, m), 4.02-4.05 (2H, m),5.28 (2H, s), 6.63 (1H, d, J=7.7 Hz), 7.31-7.48 (5H, m), 7.83 (1H, d,J=7.7 Hz)

[0840] Preparation 91

[0841] A mixture of benzyl 6-methyl-2-(4-methyl-1-piperidinyl)nicotinate(9.45 g) in methanol (80 ml) was hydrogenated over 10% palladium oncarbon (4.5 g) under atmospheric pressure of hydrogen at ambienttemperature for 5 hours.

[0842] After removal of the catalyst, the solvent was evaporated invacuo and the residue was dissolved in a ethyl acetate and dried overmagnesium sulfate. The solvent was evaporated in vacuo to give6-methyl-2-(4-methyl-1-piperidinyl)nicotinic acid (6.57 g).

[0843]¹H-NMR(DMSO-d₆):δ 0.93 (3H, d, J=6.1 Hz), 1.16-1.28 (2H, m),1.50-1.70 (3H, m), 2.37 (3H, s), 2.52-2.92 (2H, m), 3.54-3.68 (2H, m),6.77 (1H, d, J=7.7 Hz), 7.87(1H, d, J=7.7 Hz)

EXAMPLE 91

[0844] A mixture of 6-methyl-2-(4-methyl-1-piperidinyl)nicotinic acid(2.46 g), N-(4-aminophenyl)-N-[2-(2-pyridinyl)ethyl]formamide (2.41 g),1-hydroxybenzotriazole hydrate (1.61 g) and1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide (1.63 g) inN,N-dimethylformamide (25 ml) was stirred at ambient temperature for 15hours.

[0845] The reaction mixture was poured into a mixture of ethyl acetateand water, and the organic layer was washed with brine and dried overmagnesium sulfate. The solvent was evaporated in vacuo and the residuewas chromatographed on silica gel eluting with ethyl acetate. The elutedfractions containing the desired product were collected and concentratedin vacuo and the precipitate was collected by filtration to giveN-(4-{formyl[2-(2-pyridinyl)ethyl]amino}phenyl)-6-methyl-2-(4-methyl-1-piperidinyl)nicotinamide(3.49 g).

[0846]¹H-NMR(DMSO-d₆):δ 0.89 (3H, d, J=6.2 Hz), 1.16-1.22 (2H, m),1.60-1.66 (3H, m), 2.40 (3H, s), 2.74-2.95 (4H, m), 3.65-3.71 (2H, m),4.10 (2H, t, J=7.2 Hz), 6.82 (1H, d, J=7.6 Hz), 7.17-7.32 (4H, m),7.63-7.70 (4H, m), 8.35 (1H, s), 8.45-8.48 (1H, m), 10.60 (1H, s)(+)ESI-MS(m/z): 541(M+H)⁺, 563(M+Na)⁺

EXAMPLE 92

[0847] A mixture ofN-(4-{formyl[2-(2-pyridinyl)ethyl]amino}phenyl)-6-methyl-2-(4-methyl-1-piperidinyl)nicotinamide(3.45 g) and concentrated hydrochloric acid (1.93 ml) in methanol (40ml) was stirred at ambient temperature for 15 hours. The reactionmixture was evaporated in vacuo and the residue was dissolved in amixture of water and ethyl acetate and adjusted to pH 8.0 with aqueouspotassium carbonate solution.

[0848] The organic layer was washed with brine and dried over magnesiumsulfate. The solvent was concentrated in vacuo and the precipitate wascollected by filtration to give6-methyl-2-(4-methyl-1-piperidinyl)-N-(4-{[2-(2-pyridinyl)ethyl]amino}phenyl)nicotinamide(2.78 g).

[0849]¹H-NMR(DMSO-d₆):δ 0.91 (3H, d, J=6.1 Hz), 1.14-1.31 (2H, m),1.48-1.67 (2H, m), 2.39 (3H, s), 2.75-2.86 (2H, m), 2.99 (2H, t, J=7.3Hz), 3.32-3.42 (2H, m), 3.60-3.66 (2H, m), 5.57 (1H, t, J=5.7 Hz), 6.60(2H, d, J=8.8 Hz), 6.82 (1H, d, J=7.7 Hz), 7.19-7.25 (1H, m), 7.32 (1H,d, J=7.9 Hz), 7.45 (2H, d, J=8.8 Hz), 7.66-7.79 (2H, m), 8.50-8.53 (1H,m), 10.29 (1H, s)

EXAMPLE 93

[0850] The following compound was obtained in substantially the samemanner as in Example 91.

[0851]2-(Dimethylamino)-N-(4-{formyl[2-(2-pyridinyl)ethyl]amino}phenyl)benzamide

[0852]¹H-NMR(DMSO-d₆):δ 2.79 (6H, s), 2.29 (2H, t, J=7.9 Hz), 4.12 (2H,t, J=7.9 Hz), 7.05-7.13 (1H, m), 7.20-7.30 (5H, m), 7.44 (1H, d, J=7.0Hz), 7.64-7.72 (2H, m), 7.78 (2H, d, J=8.8 Hz), 8.35 (1H, s), 8.48-8.49(1H, m), 11.30 (1H,s)

EXAMPLE 94

[0853] The following compound was obtained in substantially the samemanner as in Example 92.

[0854]2-(Dimethylamino)-N-(4-{[2-(2-pyridinyl)ethyl]amino}phenyl)benzamide

[0855]¹H-NMR(DMSO-d₆):δ 2.77 (6H, s), 2.99 (2H, t, J=7.4 Hz), 3.33-3.43(2H, m), 5.56 (1H, t, J=5.7 Hz), 6.60 (2H, d, J=8.8 Hz), 7.05-7.39 (5H,m), 7.44 (2H, d, J=8.8 Hz), 7.67-7.75 (2H, m), 8.51-8.53 (1H, m), 10.95(1H, s) (+)ESI-MS(m/z): 361(M+H)⁺, 383(M+Na)⁺

EXAMPLE 95

[0856] The following compound was obtained in substantially the samemanner as in Example 91.

[0857]N-(4-{2-[6-(Acetylamino)-2-pyridinyl]ethyl)phenyl)-6-methyl-2-(4-methyl-1-piperidinyl)nicotinamide

[0858]¹H-NMR(DMSO-d₆):δ 0.98 (3H, d, J=6.1 Hz), 1.09-1.28 (2H, m),1.43-1.65 (3H, m), 2.09 (3H, s), 2.39 (3H, s), 2.75-2.87 (2H, m), 2.94(4H, s), 3.62-3.68 (2H, m), 6.82 (1H, d, J=7.6 Hz), 6.94 (1H, d, J=7.3Hz), 7.18 (2H, d, J=8.4 Hz), 7.60-7.68 (3H, m), 7.76 (1H, d, J=7.6 Hz),7.90 (1H, d, J=8.2 Hz), 10.43 (1H, s), 10.50 (1H, s)

EXAMPLE 96

[0859] A mixture ofN-(4-{2-[6-(acetylamino)-2-pyridinyl]ethyl}phenyl)-6-methyl-2-(4-methyl-1-piperidinyl)nicotinamide(610 mg) and 6N hydrochloric acid (1.5 ml) in methanol (10 ml) wasrefluxed under stirring for 8 hours. The reaction mixture was evaporatedin vacuo and the residue was dissolved in a mixture of water and ethylacetate and adjusted to pH 8.0 with aqueous potassium carbonatesolution.

[0860] The organic layer was washed with brine and dried over magnesiumsulfate. The solvent was concentrated in vacuo and the precipitate wascollected by filtration to giveN-{4-[2-(6-amino-2-pyridinyl)ethyl]phenyl}-6-methyl-2-(4-methyl-1-piperidinyl)nicotinamide(450 mg).

[0861]¹H-NMR(DMSO-d₆):δ 0.90 (3H, d, J=6.2 Hz), 1.06-1.29 (2H, m),1.48-1.65 (3H, m), 2.39 (3H, s), 2.72-2.91 (6H, m), 3.62-3.69 (2H, m),5.81 (2H, s), 6.24-6.36 (2H, m), 6.82 (1H, d, J=7.7 Hz), 7.18 (2H, d,J=8.4 Hz), 7.27 (1H, d, J=7.7 Hz), 7.62 (2H, d, J=8.4 Hz), 7.75 (1H, d,J=7.5 Hz), 10.49 (1H, s) (+)ESI-MS(m/z): 430(M+H)⁺, 452(M+Na)⁺

[0862] Preparation 92

[0863] A mixture of 2-chloro-6-methylnicotinic acid (17.2 g),N-(4-aminophenyl)-N-[2-(2-pyridinyl)ethyl]formamide (24.9 g),1-hydroxybenzotriazole hydrate (16.1 g) and1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide (16.3 g) inN,N-dimethylformamide (100 ml) was stirred at ambient temperature for 15hours.

[0864] The reaction mixture was poured into a mixture of ethyl acetateand water, and the organic layer was washed with brine and dried overmagnesium sulfate. The solvent was evaporated in vacuo and the residuewas chromatographed on silica gel eluting with ethyl acetate:methanol(95:5 v/v). The eluted fractions containing the desired product werecollected and evaporated in vacuo to give2-chloro-N-(4-{formyl[2-(2-pyridinyl)ethyl]amino}phenyl)-6-methylnicotinamide(26.8 g).

[0865]¹H-NMR(DMSO-d₆):δ 2.51 (3H, s), 2.89 (2H, t, J=7.2 Hz), 4.12 (2H,t, J=7.2 Hz), 7.18-7.34 (4H, m), 7.42 (1H, d, J=7.7 Hz), 7.64-7.76 (3H,m), 7.96 (1H, d, J=7.7 Hz), 8.14 (1H, s), 8.35-8.47 (1H, m), 10.67 (1H,s)

EXAMPLE 97

[0866] A mixture of2-chloro-N-(4-{formyl[2-(2-pyridinyl)ethyl]amino}phenyl)-6-methylnicotinamide(11.2 g) and 4-methylpiperidine(13.4 ml) in tetrahydrofuran (50 ml) wasrefluxed under stirring for 9 hours. The reaction mixture was pouredinto a mixture of ethyl acetate and water, and the organic layer waswashed with brine and dried over magnesium sulfate. The solvent wasevaporated in vacuo and the residue was chromatographed on silica geleluting with ethyl acetate: methanol (95:5 v/v). The eluted fractionscontaining the desired product were collected and the solvent wasconcentrated in vacuo and the precipitate was collected by filtration togive N-(4-{formyl[2-(2-pyridinyl)ethyl]amino}phenyl)-6-methyl-2-(4-methyl-1-piperidinyl)nicotinamide(7.21 g).

[0867]¹H-NMR(DMSO-d₆):δ 0.89 (3H, d, J=6.2 Hz), 1.16-1.22 (2H, m),1.60-1.66 (3H, m), 2.40 (3H, s), 2.74-2.95 (4H, m), 3.65-3.71 (2H, m),4.10 (2H, t, J=7.2 Hz), 6.82 (1H, d, J=7.6 Hz), 7.17-7.32 (4H, m),7.63-7.70 (4H, m), 8.35 (1H, s), 8.45-8.48 (1H, m), 10.60 (1H, s)(+)ESI-MS(m/z): 541(M+H)⁺, 563(M+Na)⁺

EXAMPLE 98

[0868] A mixture of 4-methyl-2-(4-methyl-1-piperidinyl)benzoic acid (350mg), N-2-[2-(2-pyridinyl)ethyl]-2,5-pyridinediamine (337 mg),1-hydroxybenzotriazole hydrate (241 mg) and1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide (245 mg) inN,N-dimethylformamide (15 ml) was stirred at ambient temperature for 15hours. The reaction mixture was poured into a mixture of ethyl acetateand water, and the organic layer was washed with brine and dried overmagnesium sulfate. The solvent was evaporated in vacuo and the residuewas chromatographed on silica gel eluting with ethyl acetate:methanol(97:3 v/v). The eluted fractions containing the desired product werecollected and the solvent was evaporated in vacuo. The residue wasrecrystallized from a mixture of acetone and diisopropyl ether to give4-methyl-2-(4-methyl-1-piperidinyl)-N-(6-{[2-(2-pyridinyl)ethyl]amino}-3-pyridinyl)benzamide(85 mg).

[0869]¹H-NMR(DMSO-d₆):δ 0.95 (3H, d, J=6.2 Hz), 1.29-1.51 (3H, m),1.73-7.79 (2H, m), 2.34 (3H, s), 2.72-2.83 (2H, m), 2.96-3.13 (4H, m),3.53-3.63 (2H, m), 6.47-6.56 (2H, m), 7.03 (1H, d, J=8.1 Hz), 7.16-7.31(3H, m), 7.66-7.83 (3H, m), 8.30 (1H, d, J=2.5 Hz), 8.49-8.52 (1H, m),11.64 (1H, s)

EXAMPLE 99

[0870] The following compound was obtained in substantially the samemanner as in Example 98.

[0871]2-(Dimethylamino)-4-methyl-N-(6-{[2-(2-pyridinyl)ethyl]amino}-3-pyridinyl)benzamide

[0872]¹H-NMR(DMSO-d₆):δ 2.34 (3H, s), 2.76 (6H, s), 2.99 (2H, t, J=7.4Hz), 3.54-3.64 (2H, m), 6.47-6.51 (2H, m), 6.94 (1H, d, J=8.1 Hz), 7.08(1H, s), 7.24-7.30 (2H, m), 7.64 (3H, m), 8.29 (1H, d, J=2.5 Hz),8.50-8.53 (1H, m), 11.20 (1H, s)

EXAMPLE 100

[0873] The following compound was obtained in substantially the samemanner as in Example 43.

[0874] tert-Butyl4-({[6-methyl-2-(1-pyrrolidinyl)-3-pyridinyl]carbonyl}amino)phenyl[2-(2-pyridinyl)ethyl]carbamate

[0875]¹H-NMR(DMSO-d₆):δ 1.33 (9H, s), 1.80-1.86 (4H, m), 2.34 (3H, s),2.90 (2H, t, J=7.4 Hz), 3.36-3.41 (4H, m), 3.90 (2H, t, J=7.4 Hz), 6.53(1H, d, J=7.5 Hz), 7.13-7.26 (4H, m), 7.53 (1H, d, J=7.5 Hz), 7.64-7.70(3H, m), 7.43-8.45 (1H, m), 10.31 (1H, s)

EXAMPLE 101

[0876] The following compound was obtained in substantially the samemanner as in Example 44.

[0877]6-Methyl-N-(4-{[2-(2-pyridinyl)ethyl]amino)phenyl)-2-(1-pyrrolidinyl)nicotinamide

[0878]¹H-NMR(DMSO-d₆):δ 1.79-1.85 (4H, m), 2.32 (3H, s), 2.98 (2H, t,J=7.4 Hz), 3.31-3.38 (6H, m), 5.53 (1H, m), 6.53 (1H, d, J=7.5 Hz), 6.56(2H, d, J=8.8 Hz), 7.19-7.47 (5H, m), 7.47-7.71 (1H, m), 8.50-8.53 (1H,m), 9.87 (1H, s) (+)ESI-MS(m/z): 402(M+H)⁺, 424(M+Na)⁺

EXAMPLE 102

[0879] The following compound was obtained in substantially the samemanner as in Example 43. The product was used in the next step withoutpurification.

[0880] tert-Butyl4-({[2-(diethylamino)-6-methyl-3-pyridinyl]carbonyl}amino)phenyl[2-(2-pyridinyl)ethyl]carbamate

EXAMPLE 103

[0881] The following compound was obtained in substantially the samemanner as in Example 44.

[0882]2-(Diethylamino)-6-methyl-N-(4-{[2-(2-pyridinyl)ethyl]amino}phenyl)nicotinamide

[0883]¹H-NMR(DMSO-d₆):δ 1.05 (6H, t, J=6.9 Hz), 2.36 (3H, s), 2.98 (2H,t, J=7.4 Hz), 3.30-3.40 (6H, m), 5.56 (1H, t, J=5.7 Hz), 6.57 (2H, d,J=8.9 Hz), 6.70 (1H, d, J=7.6 Hz), 7.1-7.25 (1H, m), 7.32 (1H, d, J=7.7Hz), 7.40 (2H, d, J=8.9 Hz), 7.63-7.75 (2H, m), 8.50-8.52 (1H, m), 10.43(1H, s) (+)ESI-MS(m/z): 404(M+H)⁺, 426(M+Na)⁺

EXAMPLE 104

[0884] The following compound was obtained in substantially the samemanner as in Example 43. The product was used in the next step withoutpurification.

[0885] tert-Butyl4-({[2-(diethylamino)-3-pyridinyl]carbonyl}amino)phenyl[2-(2-pyridinyl)ethyl]carbamate

EXAMPLE 105

[0886] The following compound was obtained in substantially the samemanner as in Example 44.

[0887]2-(Diethylamino)-N-(4-{[2-(2-pyridinyl)ethyl]amino}phenyl)nicotinamide

[0888]¹H-NMR(DMSO-d₆):δ 1.06 (6H, t, J=6.9 Hz), 2.99 (2H, t, J=7.4 Hz),3.34-3.44 (6H, m), 5.58 (1H, t, J=5.7 Hz), 6.59 (2H, d, J=8.8 Hz), 6.79(1H, dd, J=4.9 Hz, 7.4 Hz), 7.23-7.25 (1H, m), 7.32 (1H, d, J=7.7 Hz),7.42 (2H, d, J=8.8 Hz), 7.66-7.71 (2H, m), 8.20-8.24 (1H, m), 8.50-8.52(1H, m), 10.34 (1H, s) (+)ESI-MS(m/z): 390(M+H)⁺, 412(M+Na)⁺

EXAMPLE 106

[0889] The following compound was obtained in substantially the samemanner as in Example 97.

[0890]2-[Ethyl(methyl)amino]-N-(4-{formyl[2-(2-pyridinyl)ethyl]amino}phenyl)-6-methylnicotinamide

[0891]¹H-NMR(DMSO-d₆):δ 1.08 (3H, t, J=7.0 Hz), 2.37 (3H, s), 2.87 (3H,s), 2.91 (2H, t, J=7.3 Hz), 3.46 (2H, q, J=7.0 Hz), 4.10 (2H, t, J=7.3Hz), 6.63 (1H, d, J=7.6 Hz), 7.17-7.30 (3H, m), 7.59 (1H, d, J=7.6 Hz),7.64-7.77 (3H, m), 8.34 (1H, s), 7.46-8.48 (1H, m), 10.47 (1H, s)

EXAMPLE 107

[0892] The following compound was obtained in substantially the samemanner as in Example 92.

[0893]2-[Ethyl(methyl)amino]-6-methyl-N-(4-{[2-(2-pyridinyl)ethyl]amino}phenyl)nicotinamide

[0894]¹H-NMR(DMSO-d₆):δ 1.05 (3H, t, J=6.9 Hz), 2.35 (3H, s), 2.86 (3H,s), 2.98 (2H, t, J=7.4 Hz), 3.33-3.48 (4H, m), 5.56 (1H, br.s),6.55-6.63 (3H, m), 7.19-7.25 (1H, m), 7.31 (1H, d, J=7.7 Hz), 7.40 (2H,d, J=8.8 Hz), 7.55 (1H, d, J=7.5 Hz), 7.66-7.75 (1H, m), 8.50-8.53 (1H,m), 10.01 (1H, s) (+)ESI-MS(m/z): 390(M+H)⁺, 412(M+Na)⁺

[0895] Preparation 93

[0896] The following compound was obtained in substantially the samemanner as in Preparation 92.

[0897]2,6-Dichloro-N-(4-{formyl[2-(2-pyridinyl)ethyl]amino}phenyl)nicotinamide

[0898]¹H-NMR(DMSO-d₆):δ 2.92 (2H, t, J=7.3 Hz), 4.13 (2H, t, J=7.3 Hz),7.21-7.37 (3H, m), 7.65-7.80 (5H, m), 8.21 (1H, d, J=8.0 Hz), 8.23 (1H,s), 8.48-8.51 (1H, m), 10.78 (1H, s)

EXAMPLE 108

[0899] The following compound was obtained in substantially the samemanner as in Example 97.

[0900]N-(4-{Formyl[2-(2-pyridinyl)ethyl]amino}phenyl)-2,6-bis(4-methyl-1-piperidinyl)nicotinamide

[0901]¹H-NMR(DMSO-d₆):δ 0.90-0.95 (6H, m), 10.2-1.34 (4H, m), 1.51-1.71(6H, m), 2.76-2.95 (4H, m), 3.30-3.47 (4H, m), 4.10 (2H, t, J=7.2 Hz),4.32-4.39 (4H, m), 6.48 (1H, d, J=8.7 Hz), 7.16-7.30 (4H, m), 7.63-7.86(4H, m), 8.12 (1H, s), 8.45 (1H, m), 10.85 (1H, s)

EXAMPLE 109

[0902] The following compound was obtained in substantially the samemanner as in Example 92.

[0903]2,6-Bis(4-methyl-1-piperidinyl)-N-(4-{[2-(2-pyridinyl)ethyl]amino}phenyl)nicotinamide

[0904]¹H-NMR(DMSO-d₆):δ 0.90-0.94 (6H, m), 1.02-1.71 (10H, m), 2.74-2.89(4H, m), 2.98 (2H, t, J=7.3 Hz), 3.33-3.42 (6H, m), 4.30-4.37 (2H, m),5.52 (1H, s), 6.48 (1H, J=8.6 Hz), 6.58 (2H, d, J=8.8 Hz), 7.15-7.25(1H, m), 7.32 (1H, d, J=7.7 Hz), 7.42 (2H, d, J=8.8 Hz), 7.67-7.75 (1H,m), 7.84 (1H, d, J=8.6 Hz), 8.50-8.53 (1H, m), 10.53 (1H, s)(+)ESI-MS(m/z): 513(M+H)⁺, 535(M+Na)⁺

[0905] Preparation 94

[0906] The following compound was obtained in substantially the samemanner as in Preparation 92.

[0907]2-Chloro-6-methyl-N-(6-{[2-(2-pyridinyl)ethyl]amino}-3-pyridinyl)nicotinamide

[0908]¹H-NMR(DMSO-d₆):δ 2.51 (3H, s), 3.00 (2H, t, J=7.4 Hz), 3.54-3.64(2H, m), 6.48-6.58 (2H, m), 7.21-7.30 (2H, m), 7.39 (1H, d, J=7.7 Hz),7.66-7.73 (2H, m), 7.93 (1H, d, J=7.6 Hz), 8.27 (1H, d, J=2.5 Hz),8.50-8.53 (1H, m), 10.27 (1H, s)

EXAMPLE 110

[0909] The following compound was obtained in substantially the samemanner as in Example 97.

[0910]6-Methyl-2-(4-methyl-1-piperidinyl)-N-(6-{[2-(2-pyridinyl)ethyl]amino}-3-pyridinyl)nicotinamide

[0911]¹H-NMR(DMSO-d₆):δ 0.90 (3H, d, J=6.2 Hz), 1.14-1.29 (2H, m),1.44-1.67 (3H, m), 2.39 (3H, s), 2.75-2.87 (2H, m), 2.99 (2H, t, J=7.4Hz), 3.53-3.69 (4H, m), 6.46-6.51 (2H, m), 6.80 (1H, d, J=7.6 Hz),7.18-7.25 (1H, m), 7.28 (1H, d, J=7.8 Hz), 7.66-7.75 (3H, m), 8.27 (1H,d, J=2.5 Hz), 8.49-8.51 (1H, m), 10.24 (1H, s) (+)ESI-MS(m/z):431(M+H)⁺, 453(M+Na)⁺

EXAMPLE 111

[0912] The following compound was obtained in substantially the samemanner as in Example 97.

[0913]6-Methyl-2-(1-piperidinyl)-N-(6-{[2-(2-pyridinyl)ethyl]amino}-3-pyridinyl)nicotinamide

[0914]¹H-NMR(DMSO-d₆):δ 1.55 (6H, s), 2.39 (3H, s), 2.98 (2H, t, J=7.4Hz), 3.22 (4H, m), 3.52-3.62 (2H, m), 6.46-6.50 (2H, m), 6.82 (1H, d,J=7.6 Hz), 7.21-7.25 (1H, m), 7.28 (1H, d, J=7.7 Hz), 7.66-7.07 (3H, m),8.28 (1H, d, J=2.5 Hz), 8.49-8.51 (1H, m), 10.30 (1H, s) (+)ESI-MS(m/z):417(M+H)⁺, 439(M+Na)⁺

[0915] Preparation 95

[0916] A solution of 2-chloro-6-methylnicotinoyl chloride (1.9 g) intetrahydrofuran (5 ml) was added to a mixture of1-(4-aminophenyl)-3-(2-pyridinyl)propan-1-one (2.26 g) and triethylamine(4.04 g) in tetrahydrofuran (50 ml) at ambient temperature. The mixturewas stirred at ambient temperature for 5 hours. The resultant mixturewas poured into a mixture of ethyl acetate and water, and the organiclayer was washed with a 5% potassium carbonate solution and brine anddried over magnesium sulfate. The solvent was evaporated in vacuo andthe residue was recrystallized from a mixture of ethyl acetate andn-hexane to give2-chloro-6-methyl-N-{4-[3-(2-pyridinyl)propanoyl]phenyl}nicotinamide(3.11 g).

[0917]¹H-NMR(DMSO-d₆):δ 3.11 (2H, t, J=7.2 Hz), 3.47 (2H, t, J=7.2 Hz),7.16-7.22 (1H, m), 7.34 (1H, d, J=7.8 Hz), 7.43 (1H, d, J=7.7 Hz),7.65-7.74 (1H, m), 7.83 (2H, d, J=8.7 Hz), 7.98-8.05 (3H, m), 8.44-8.47(1H, s), 10.90 (1H, s)

EXAMPLE 112

[0918] A mixture of2-chloro-6-methyl-N-{4-[3-(2-pyridinyl)propanoyl]phenyl}nicotinamide(1.52 g) and 4-methylpiperidine (1.9 ml) in tetrahydrofuran (10 ml) wasrefluxed under stirring for 7 hours. The reaction mixture was pouredinto a mixture of ethyl acetate and water, and the organic layer waswashed with brine and dried over magnesium sulfate. The solvent wasconcentrated in vacuo and the precipitate was collected by filtration togive6-methyl-2-(4-methyl-1-piperidinyl)-N-{4-[3-(2-pyridinyl)propanoyl]phenyl}nicotinamide(1.346 g).

[0919]¹H-NMR(DMSO-d₆):δ 0.88 (3H, d, J=6.1 Hz), 1.14-1.26 (2H, m),1.47-1.64 (3H, m), 2.40 (3H, s), 2.76-2.87 (2H, m), 3.11 (2H, t, J=7.2Hz), 3.62 (2H, t, J=7.2 Hz), 4.01-4.05 (2H, m), 6.83 (1H, J=7.7 Hz),7.15-7.22 (1H, m), 7.34 (1H, d, J=7.7 Hz), 7.65-7.79 (2H, m), 7.85 (2H,d, J=8.0 Hz), 8.02 (2H, d, J=8.0 Hz), 8.45-8.47 (1H, m), 10.81 (1H, s)(+)ESI-MS(m/z): 443(M+H)⁺, 465(M+Na)⁺

EXAMPLE 113

[0920] Sodium borohydrate (182 mg) was added to a solution of6-methyl-2-(4-methyl-1-piperidinyl)-N-{4-[3-(2-pyridinyl)propanoyl]phenyl}nicotinamide(1.06 g) in methanol (30 ml) at ambient temperature under stirring. Themixture was stirred at ambient temperature for 4 hours. The resultantsolution was evaporated in vacuo and the residue was dissolved in amixture of ethyl acetate and water. The organic layer was washed with a5% aqueous potassium carbonate solution and brine and dried overmagnesium sulfate. The solvent was evaporated in vacuo and the residuewas recrystallized from a mixture of ethyl acetate and diisopropyl etherto giveN-{4-[1-hydroxy-3-(2-pyridinyl)propyl]phenyl}-6-methyl-2-(4-methyl-1-piperidinyl)nicotinamide(738 mg).

[0921]¹H-NMR(DMSO-d₆):δ 0.89 (3H, d, J=6.1 Hz), 1.02-1.29 (2H, m),1.48-1.66 (3H, m), 1.93-2.04 (2H, m), 2.63-2.87 (4H, m), 3.62-3.69 (2H,m), 4.50-4.58 (1H, m), 5.27 (1H, d, J=4.4 Hz), 6.83 (1H, d, J=7.6 Hz),7.14-7.24 (2H, m), 7.31 (2H, d, J=7.6 Hz), 7.63-7.71 (3H, m), 7.76 (1H,d, J=7.6 Hz), 8.46 (1H, d, J=4.5 Hz), 10.53 (1H, s) (−)ESI-MS(m/z):443(M−H)⁻

EXAMPLE 114

[0922] A solution ofN-{4-[1-hydroxy-3-(2-pyridinyl)propyl]phenyl}-6-methyl-2-(4-methyl-1-piperidinyl)nicotinamide(610 mg) in methanol (30 ml) and 4N hydrogen chloride in 1,4-dioxane(1.5 ml) was hydrogenated over 10% palladium on carbon (300 mg) under anatmospheric pressure of hydrogen at ambient temperature under stirringfor 10 hours. After removal of the catalyst, the solvent was evaporatedin vacuo. The residue was dissolved in a mixture of water and ethylacetate and adjusted to pH 8.0 with a 5% aqueous potassium carbonatesolution. The organic layer was washed with brine and dried overmagnesium sulfate. The solvent was evaporated in vacuo and the residuewas chromatographed on silica gel eluting with ethyl acetate: n-hexane(6:4 v/v). The eluted fractions containing the desired product werecollected and the solvent was evaporated. The residue was crystallizedfrom a mixture of diisopropyl ether and n-hexane to give6-methyl-2-(4-methyl-1-piperidinyl)-N-{4-[3-(2-pyridinyl)propyl]phenyl}nicotinamide(190 mg).

[0923]¹H-NMR(DMSO-d₆):δ 0.98 (3H, d, J=6.1 Hz), 1.05-1.29 (2H, m),1.48-1.92 (3H, m), 1.92-2.04 (2H, m), 2.39 (3H, s ), 2.51-2.87 (6H, m),3.62-3.69 (2H, m), 6.82 (1H, d, J=7.7 Hz), 7.16-7.30 (4H, m), 7.62-7.85(4H, m), 8.48 (1H, d, J=4.4 Hz), 10.51 (1H, s) (+)ESI-MS(m/z):429(M+H)⁺, 451(M+Na)⁺

[0924] Preparation 96

[0925] A mixture of 2-(1H-pyrazol-1-yl)ethanol (6.76 g) and potassiumtert-butoxide (6.75 g) in tetrahydrofuran (100 ml) was stirred atambient temperature for an hour. A solution of 1-fluoro-4-nitrobenzene(7.1 g) in tetrahydrofuran (5 ml) was added to the above mixture andrefluxed under stirring for 2.5 hours. The reaction mixture was pouredinto a mixture of ethyl acetate and water, and the organic layer waswashed with brine and dried over magnesium sulfate. The solvent wasconcentrated in vacuo and the precipitate was collected by filtration togive 1-[2-(4-nitrophenoxy)ethyl]-1H-pyrazole (10.75 g).

[0926]¹H-NMR(DMSO-d₆):δ 4.47-4.60 (4H, m), 6.27 (1H, m), 7.08-7.16 (2H,m), 7.49 (1H, d, J=1.7 Hz), 7.81 (1H, d, J=2.0 Hz), 8.16-8.23 (2H, m)

[0927] Preparation 97

[0928] A mixture of 1-[2-(4-nitrophenoxy)ethyl]-1H-pyrazole (1.63 g) inmethanol (25 ml) and tetrahydrofuran (25 ml) was hydrogenated over 10%palladium on carbon (0.8 g) under atmospheric pressure of hydrogen atambient temperature for 6 hours. After removal of the catalyst byfiltration, the solvent was evaporated in vacuo to give4-[2-(1H-pyrazol-1-yl)ethoxy]phenylamine (1.4 g).

[0929]¹H-NMR(DMSO-d₆):δ 4.15-4.19 (2H, m), 4.39-4.64 (2H, m), 4.64 (2H,s), 6.23 (1H, s),6.45-6.51 (2H, m), 6.59-6.68 (2H, m), 7.45 (1H, s),7.74 (1H, s)

[0930] Preparation 98

[0931] A mixture of 2-(1H-pyrazol-1-yl)ethanol (5.41 g) and potassiumtert-butoxide (5.41 g) in tetrahydrofuran (50 ml) was stirred at ambienttemperature for an hour. 2-Chloro-5-nitropyridine (6.38 g) was added tothe above mixture and the resultant mixture was stirred at ambienttemperature for 6.5 hours. The reaction mixture was poured into amixture of ethyl acetate and water, and the organic layer was washedwith brine and dried over magnesium sulfate. The solvent wasconcentrated in vacuo and the residue was chromatographed on silica geleluting with ethyl acetate and n-hexane (6:4 v/v). The fraction wasconcentrated in vacuo and the precipitate was collected by filtration togive 5-nitro-2-[2-(1H-pyrazol-1-yl)ethoxy]pyridine (6.48 g).

[0932]¹H-NMR(DMSO-d₆):δ 4.55 (2H, t, J=4.9 Hz),4.76 (2H, t, J=4.9 Hz),6.23-6.25 (1H, m),7.10 (1H, d, J=9.2 Hz), 7.45 (1H, d, J=1.7 Hz), 7.78(1H, d, J=2.3 Hz), 8.46 (1H, dd, J=2.8 Hz, 9.2 Hz), 9.07 (1H, d, J=2.8Hz)

[0933] Preparation 99

[0934] The following compound was obtained in substantially the samemanner as in Preparation 97.

[0935] 6-[2-(1H-Pyrazol-1-yl)ethoxy]-3-pyridinamine

[0936]¹H-NMR(DMSO-d₆):δ 4.43 (4H, m), 4.79 (2H, s), 6.22-6.24 (1H, m),6.50 (1H, d, J=8.7 Hz), 7.99 (1H, dd, J=2.8 Hz, 8.7 Hz), 7.43 (1H, d,J=3.4 Hz), 7.49 (1H, d, J=2.8 Hz), 7.71 (1H, d, J=2.0 Hz)

[0937] Preparation 100

[0938] A mixture of 1-(2-chloroethoxy)-4-nitrobenzene (2.82 g) and1,2,4-triazole sodium salt (1.78 g) in N,N-dimethylformamide (30 ml) wasstirred at 75-80° C. for 5 hours. The reaction mixture was poured into amixture of ethyl acetate and water, and the organic layer was washedwith brine and dried over magnesium sulfate. The solvent wasconcentrated in vacuo and the precipitate was collected by filtration togive 1-[2-(4-nitrophenoxy)ethyl]-1H-1,2,4-triazole (2.27 g).

[0939]¹H-NMR(DMSO-d₆):δ 4.92 (2H, t, J=4.8 Hz), 4.65 (2H, t, J=4.8 Hz),7.08-7.20 (2H, m), 8.00 (1H, s), 8.15-8.23 (2H, m), 8.60 (1H, s)(+)ESI-MS(m/z): 235(M+H)⁺, 257(M+Na)⁺

[0940] Preparation 101

[0941] The following compound was obtained in substantially the samemanner as in Preparation 97.

[0942] 4-[2-(1H-1,2,4-Triazol-1-yl)ethoxy]phenylamine

[0943]¹H-NMR(DMSO-d₆):δ 4.18 (2H, t, J=5.1 Hz), 4.50 (2H, t, J=5.1 Hz),4.65 (2H, s), 6.43-6.53 (2H, m), 6.57-6.71 (2H, m), 7.99 (1H, s), 8.54(1H,s)

[0944] Preparation 102

[0945] A mixture of N-(2-chloroethyl)-4-nitroaniline hydrochloride (12.0g), 1,2,4-triazole sodium salt (6.45 g) and potassium carbonate (8.38 g)in N,N-dimethylformamide (30 ml) was stirred at 75-80° C. for 6 hours.

[0946] The reaction mixture was poured into a mixture of ethyl acetateand water, and the organic layer was washed with brine and dried overmagnesium sulfate. The solvent was evaporated in vacuo and the residuewas chromatographed on silica gel eluting with ethyl acetate:methanol(94:6 v/v). The eluted fractions were concentrated in vacuo and theprecipitate was collected by filtration to giveN-(4-nitrophenyl)-N-[2-(1H-1,2,4-triazol-1-yl)ethyl]amine (4.7 g).

[0947]¹H-NMR(DMSO-d₆):δ 3.60-3.69 (2H, m), 4.37 (2H, t, J=5.8 Hz),6.61-6.69 (2H, m), 7.35 (1H, t, J=6.0 Hz), 7.95-8.02 (3H, m), 8.45 (1H,s)

[0948] Preparation 103

[0949] The following compound was obtained in substantially the samemanner as in Preparation 97.

[0950] N-[2-(1H-1,2,4-Triazol-1-yl)ethyl]-1,4-benzenediamine

[0951]¹H-NMR(DMSO-d₆):δ 3.30-3.39 (2H, m), 4.29 (2H, t, J=6.0 Hz), 4.32(2H, s), 4.85 (1H, t, J=6.3 Hz), 6.35-6.47 (4H, m), 7.98 (1H, s), 8.45(1H, s)

[0952] Preparation 104

[0953] A mixture of (3-bromopropyl)benzene (10.0 g) and 1,2,4-triazolesodium salt (6.4 g) in N,N-dimethylformamide (50 ml) was stirred at75-80° C. for 8.5 hours. The reaction mixture was poured into a mixtureof ethyl acetate and water, and the organic layer was washed with brineand dried over magnesium sulfate. The solvent was evaporated in vacuo togive 1-(3-phenylpropyl)-1H-1,2,4-triazole (8.56 g).

[0954]¹H-NMR(DMSO-d₆):δ 2.17-2.28 (2H, m), 2.63 (2H, t, J=7.2 Hz), 4.12(2H, t, J=7.0 Hz), 7.14-7.35 (5H, m), 7.99 (1H, s), 8.14 (1H, s)

[0955] Preparation 105

[0956] To a solution of fuming nitric acid (d=1.52) (40 ml) wasportionwise added a 1-(3-phenylpropyl)-1H-1,2,4-triazole (8.5 g) at atemperature from −30° C. to −5° C. with stirring and the mixture wasstirred at the same temperature for 20 minutes. The reaction mixture waspoured into ice-water. The mixture was adjusted to pH 8.0 with anaqueous potassium carbonate solution and extracted with ethyl acetate.The organic layer was washed with brine and dried over magnesiumsulfate. The solvent was evaporated in vacuo and the residue waschromatographed on silica gel eluting with ethyl acetate. The elutedfractions were evaporated in vacuo to give1-[3-(4-nitrophenyl)propyl]-1H-1,2,4-triazole (4.67 g).

[0957]¹H-NMR(DMSO-d₆):δ 2.08-2.23 (2H, m), 2.68-2.76 (2H, m), 4.19 (2H,t, J=6.9 Hz), 7.51 (2H, d, J=8.6 Hz), 8.00 (1H, s), 8.18 (2H, d, J=9.6Hz), 8.55 (1H, s)

[0958] Preparation 106

[0959] The following compound was obtained in substantially the samemanner as in Preparation 97.

[0960] 4-[3-(1H-1,2,4-Triazol-1-yl)propyl]phenylamine

[0961]¹H-NMR(DMSO-d₆):δ 1.90-2.03 (2H, m), 2.27-2.37 (2H, m), 4.18-4.23(2H, m), 4.86 (2H, s), 6.45-6.63 (2H, m), 6.82-6.93 (2H, m), 7.98 (1H,s), 8.52 (1H, s)

[0962] Preparation 107

[0963] The following compound was obtained in substantially the samemanner as in Preparation 92.

[0964]2-Chloro-6-methyl-N-{4-[2-oxo-2-(2-pyridinylamino)ethyl]phenyl}nicotinamide

[0965]¹H-NMR(DMSO-d₆):δ 2.52 (3H, s), 3.71 (2H, s), 7.02-7.12 (1H, m),7.32-7.42 (3H, m), 7.63-7.76 (3H, m), 7.94 (1H, d, J=7.7 Hz), 8.06 (1H,d, J=8.3 Hz), 8.30-8.33 (1H, m), 10.54 (1H, s), 10.67 (1H, s)

EXAMPLE 115

[0966] The following compound was obtained in substantially the samemanner as in Example 113.

[0967]6-Methyl-2-(4-methyl-1-piperidinyl)-N-{4-[2-oxo-2-(2-pyridinylamino)ethyl]phenyl}nicotinamide

[0968]¹H-NMR(DMSO-d₆):δ 0.88 (3H, d, J=6.2 Hz), 1.11-1.27 (2H, m),1.42-1.65 (3H, m), 2.39 (3H, s), 2.75-2.87 (2H, m), 3.69 (2H, s),3.62-3.69 (2H, m), 6.82 (1H, d, J=7.7 Hz), 7.06-7.12 (1H, m), 7.31 (2H,d, J=8.4 Hz), 7.66 (2H, d, J=8.4 Hz), 7.69-7.76 (2H, m), 8.06 (1H, d,J=8.4 Hz), 8.30-8.33 (1H, m), 10.53 (1H, s), 10.67 (1H, s)(+)ESI-MS(m/z): 444(M+H)⁺, 466(M+Na)⁺

EXAMPLE 116

[0969] A mixture of 2-(dimethylamino)-4-methylbenzoic acid (215 mg),2-(4-aminophenyl)-N-(2-pyridinyl)acetamide (284 mg),1-hydroxybenzotriazole (170 mg) and1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide (196 mg) inN,N-dimethylformamide (10 ml) was stirred at ambient temperature for 15hours.

[0970] The reaction mixture was poured into a mixture of ethyl acetateand water, and the organic layer was washed with brine and dried overmagnesium sulfate. The solvent was evaporated in vacuo and the residuewas chromatographed on silica gel eluting with ethyl acetate: n-hexane(7:3 v/v). The eluted fractions containing the desired product werecollected and the solvent was evaporated in vacuo. The residue wascrystallized from a mixture of ethyl acetate and diisopropyl ether togive2-(dimethylamino)-4-methyl-N-{4-[2-oxo-2-(2-pyridinylamino)ethyl]phenyl}benzamide(205 mg).

[0971]¹H-NMR(DMSO-d₆):δ 2.34 (3H, s), 2.76 (6H, s), 3.69 (2H, s), 6.95(1H, d, J=7.8 Hz), 7.06-7.12 (2H, m), 7.32 (2H, d, J=8.3 Hz), 7.65-7.80(4H, m), 8.02 (1H, d, J=8.3 Hz), 8.32 (1H, d, J=3.9 Hz), 10.68 (1H, s),11.49 (1H, s) (+)ESI-MS(m/z): 389(M+H)⁺, 411(M+Na)⁺

EXAMPLE 117

[0972] The following compound was obtained in substantially the samemanner as in Example 116.

[0973]4-Methyl-2-(4-methyl-1-piperidinyl)-N-{4-[2-oxo-2-(2-pyridinylamino)ethyl]phenyl}benzamide

[0974]¹H-NMR(DMSO-d₆):δ 0.96 (3H, d, J=5.9 Hz), 1.14-1.49 (3H, m),1.72-1.78 (2H, m), 2.35 (3H, s), 2.73-2.84 (2H, m), 3.08-3.13 (2H, m),3.70 (2H, s), 7.03-7.12 (2H, m), 7.18 (1H, s), 7.34 (2H, d, J=8.4 Hz),7.70 (2H, d, J=8.4 Hz), 7.72-7.84 (2H, m), 8.07 (1H, d, J=8.4 Hz), 8.32(1H, d, J=3.8 Hz), 10.70 (1H, s), 11.94 (1H, s) (+)ESI-MS(m/z):443(M+H)⁺, 465(M+Na)⁺

EXAMPLE 118

[0975] The following compound was obtained in substantially the samemanner as in Example 116.

[0976]N-[4-({[6-Methyl-2-(4-methyl-1-piperidinyl)-3-pyridinyl]carbonyl}amino)benzyl]-2-pyridinecarboxamide

[0977]¹H-NMR(DMSO-d₆):δ 0.88 (3H, d, J=6.2 Hz), 1.14-1.27 (2H, m),1.42-1.64 (3H, m), 2.39 (3H, s), 2.74-2.86 (2H, m), 3.61-3.67 (2H, m),4.46 (2H, d, J=6.4 Hz), 6.82 (1H, d, J=7.6 Hz), 7.30 (2H, d, J=8.4 Hz),7.58-7.77 (4H, m), 7.96-8.08 (2H, m), 8.66 (1H, d, J=4.8 Hz), 9.32 (1H,t, J=6.4 Hz), 10.53 (1H, s) (+)ESI-MS(m/z): 444(M+H)⁺, 466(M+Na)⁺

EXAMPLE 119

[0978] The following compound was obtained in substantially the samemanner as in Example 116.

[0979]N-(4-{[4-Methyl-2-(4-methyl-1-piperidinyl)benzoyl]amino}benzyl)-2-pyridinecarboxamide

[0980]¹H-NMR(DMSO-d₆):δ 0.94 (3H, d, J=6.0 Hz), 1.17-1.50 (3H, m),1.71-1.77 (2H, m), 2.28 (3H, s), 2.65-2.83 (2H, m), 3.07-3.13 (2H, m),4.48 (2H, d, J=6.3 Hz), 7.05 (1H, d, J=7.9 Hz), 7.17 (1H, s), 7.33 (2H,d, J=8.4 Hz), 7.59-7.71 (3H, m), 7.82 (1H, d, J=7.9 Hz), 7.97-8.09 (2H,m), 8.66 (1H, d, J=4.7 Hz), 9.33 (1H, t, J=6.3 Hz), 11.93 (1H, s)(+)ESI-MS(m/z): 443(M+H)⁺, 465(M+Na)⁺

EXAMPLE 120

[0981] A mixture of 6-methyl-2-(4-methyl-1-piperidinyl)nicotinic acid(350 mg), 4-[2-(1H-pyrazol-1-yl)ethoxy]phenylamine (320 mg),1-hydroxybenzotriazole hydrate (242 mg) and1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide (245 mg) inN,N-dimethylformamide (20 ml) was stirred at ambient temperature for 15hours.

[0982] The reaction mixture was poured into a mixture of ethyl acetateand water, and the organic layer was washed with brine and dried overmagnesium sulfate. The solvent was evaporated in vacuo and the residuewas chromatographed on silica gel eluting with ethyl acetate: n-hexane(6:4 v/v). The eluted fractions containing the desired product werecollected and concentrated in vacuo and the precipitate was collected byfiltration to give6-methyl-2-(4-methyl-1-piperidinyl)-N-{4-[2-(1H-pyrazol-1-yl)ethoxy]phenyl}nicotinamide(532 mg).

[0983]¹H-NMR(DMSO-d₆):δ 0.89 (3H, d, J=6.1 Hz), 1.09-1.20 (2H, m),1.42-1.64 (3H, m), 2.38 (3H, s), 2.73-2.85 (2H, m), 3.62-3.68 (2H, m),4.30 (2H, t, J=5.2 Hz),4.48 (2H, t, J=5.2 Hz), 6.25 (1H, m), 6.81 (1H,d, J=7.6 Hz), 6.90 (2H, d, J=9.0 Hz), 7.46 (1H, d, J=1.7 Hz), 7.62 (2H,d, J=9.0 Hz), 7.73 (1H, d, J=7.6 Hz), 7.78 (1H, d, J=2.4 Hz), 10.40 (1H,s) (+)ESI-MS(m/z): 420(M+H)⁺, 442(M+Na)⁺

EXAMPLE 121

[0984] The following compound was obtained in substantially the samemanner as in Example 120.

[0985]4-Methyl-2-(4-methyl-1-piperidinyl)-N-{4-[2-(1H-pyrazol-1-yl)ethoxy]phenyl}benzamide

[0986]¹H-NMR(DMSO-d₆):δ 0.94 (3H, d, J=6.1 Hz), 1.21-1.50 (3H, m),1.70-1.76 (2H, m), 2.71-2.82 (2H, m), 3.06-3.12 (2H, m), 4.34 (2H, t,J=5.2 Hz), 4.49 (2H, t, J=5.2 Hz), 6.25 (1H, m), 6.93 (2H, d, J=9.0 Hz),7.03 (1H, d, J=8.0 Hz), 7.16 (1H, s), 7.46 (1H, d, J=1.3 Hz), 7.65 (2H,d, J=9.0 Hz), 7.78 (1H, s), 7.81 (1H, d, J=8.0 Hz), 11.80 (1H, s)(+)ESI-MS(m/z): 419(M+H)⁺, 441(M+Na)⁺

EXAMPLE 122

[0987] The following compound was obtained in substantially the samemanner as in Example 120.

[0988]2-(Dimethylamino)-4-methyl-N-(4-[2-(1H-pyrazol-1-yl)ethoxy]phenyl}benzamide

[0989]¹H-NMR(DMSO-d₆):δ 2.33 (3H, s), 2.76 (6H, s), 4.31 (2H, t, J=5.3Hz), 4.49 (2H, t, J=5.3 Hz), 6.24-6.26 (1H, m), 6.88-6.96 (3H, m), 7.07(1H, s), 7.47 (1H, d, J=1.6 Hz), 7.64-7.67 (2H, m), 7.78 (1H, d, J=2.2Hz), 11.35 (1H, s) (+)ESI-MS(m/z): 365(M+H)⁺, 387(M+Na)⁺

EXAMPLE 123

[0990] A mixture of 6-methyl-2-(4-methyl-1-piperidinyl)nicotinic acid(235 mg), 4-[2-(1H-1,2,4-triazol-1-yl)ethoxy]aniline (215 mg),1-hydroxybenzotriazole (142 mg) and1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide (163 mg) inN,N-dimethylformamide (20 ml) was stirred at ambient temperature for 15hours.

[0991] The reaction mixture was poured into a mixture of ethyl acetateand water, and the organic layer was washed with brine and dried overmagnesium sulfate. The solvent was evaporated in vacuo and the residuewas chromatographed on silica gel eluting with ethyl acetate:methanol(94:6 v/v). The eluted fractions containing the desired product werecollected and concentrated in vacuo and the precipitate was collected byfiltration to give6-methyl-2-(4-methyl-1-piperidinyl)-N-{4-[2-(1H-1,2,4-triazol-1-yl)ethoxy]phenyl)nicotinamide(336 mg).

[0992]¹H-NMR(DMSO-d₆):δ 0.89 (3H, d, J=6.2 Hz), 1.09-1.26 (3H, m),1.45-1.64 (2H,m), 2.39 (3H, s), 2.60-2.89 (2H, m), 3.34-3.62 (2H, m),4.32 (2H, t, J=5.0 Hz), 4.58 (2H, t, J=5.0 Hz), 6.81 (1H, d, J=7.6 Hz),6.40 (2H, d, J=9.0 Hz), 7.62 (2H, d, J=9.0 Hz), 7.73 (2H, J=7.6 Hz),7.95 (1H, s), 8.58 (1H, s), 10.40 (1H, s)

EXAMPLE 124

[0993] The following compound was obtained in substantially the samemanner as in Example 123.

[0994]4-Chloro-2-(dimethylamino)-N-{4-[2-(1H-1,2,4-triazol-1-yl)ethoxy]phenyl}benzamide

[0995]¹H-NMR(DMSO-d₆):δ 2.79 (6H, s), 4.33 (2H, t, J=4.9 Hz), 4.57 (2H,t, J=4.9 Hz), 6.90 (2H, d, J=8.7 Hz), 7.00 (1H, d, J=8.2 Hz), 7.08 (1H,s), 7.51 (1H, d, J=8.2 Hz), 7.60 (2H, d, J=8.8 Hz), 8.00 (1H, s), 8.58(1H, s), 10.59 (1H, s) (+)ESI-MS(m/z): 386(M+H)⁺, 408(M+Na)⁺

EXAMPLE 125

[0996] The following compound was obtained in substantially the samemanner as in Example 123.

[0997]6-Methyl-2-(4-methyl-1-piperidinyl)-N-(4-{[2-(1H-1,2,4-triazol-1-yl)ethyl]amino}phenyl)nicotinamide

[0998]¹H-NMR(DMSO-d₆):δ 0.90 (3H, d, J=6.1 Hz), 1.14-1.30 (2H, m),1.46-1.67 (3H, m), 2.39 (3H, s), 2.73-2.89 (2H, m), 3.41-3.50 (2H, m),3.60-3.66 (2H, m), 4.33 (2H, t, J=6.1 Hz), 5.65 (1H, t, J=6.0 Hz), 6.57(2H, d, J=8.8 Hz), 6.82 (1H, d, J=7.6 Hz), 7.45 (2H, d, J=8.8 Hz), 7.65(1H, d, J=7.6 Hz), 7.99 (1H, s), 8.48 (1H, s), 10.28 (1H, s)(+)ESI-MS(m/z): 420(M+H)⁺, 442(M+Na)⁺

EXAMPLE 126

[0999] The following compound was obtained in substantially the samemanner as in Example 123.

[1000]4-Methyl-2-(4-methyl-1-piperidinyl)-N-(4-{[2-(1H-1,2,4-triazol-1-yl)ethyl]amino}phenyl)benzamide

[1001]¹H-NMR(DMSO-d₆):δ 0.96 (3H, d, J=6.0 Hz), 1.26-1.51 (3H, m),1.72-1.78 (2H, m), 2.34 (3H, m), 2.72-2.89 (2H, m), 3.06-3.12 (2H, m),4.34 (2H, t, J=6.1 Hz), 5.66 (1H, t, J=6.0 Hz), 6.60 (2H, d, J=8.8 Hz),7.03 (1H, d, J=8.0 Hz), 7.16 (1H, s), 7.49 (2H, d, J=8.8 Hz), 7.83 (1H,d, J=8.0 Hz), 7.99 (1H, s), 8.49 (1H, s), 11.73 (1H, s) (+)ESI-MS(m/z):419(M+H)⁺, 441(M+Na)⁺

EXAMPLE 127

[1002] The following compound was obtained in substantially the samemanner as in Example 123.

[1003]2-(Dimethylamino)-4-methyl-N-(4-{[2-(1H-1,2,4-triazol-1-yl)ethyl]amino}phenyl)benzamide

[1004]¹H-NMR(DMSO-d₆):δ 2.33 (3H, s), 2.75 (6H, s), 3.41-3.50 (2H, m),4.33 (2H, t J=6.1 Hz), 5.64 (1H, t, J=6.1 Hz), 6.57 (2H, d, J=8.8 Hz),7.08 (1H, s), 7.44 (2H, d, J=8.8 Hz), 7.66 (1H, d, J=8.0 Hz), 7.99 (1H,s), 8.48 (1H, s), 11.19 (1H, s) (+)ESI-MS(m/z): 365(M+H)⁺, 387(M+Na)⁺

EXAMPLE 128

[1005] The following compound was obtained in substantially the samemanner as in Example 123.

[1006]6-Methyl-2-(4-methyl-1-piperidinyl)-N-{4-[3-(1H-1,2,4-triazol-1-yl)propyl[phenyl}nicotinamide

[1007]¹H-NMR(DMSO-d₆):δ 0.88 (3H, d, J=6.1 Hz), 1.02-1.28 (2H, m),1.48-1.65 (3H, m), 2.39 (3H, s), 2.49-2.56 (2H, m), 3.57-3.69 (2H, m),4.01-4.05 (2H, m), 4.19 (2H, t, J=7.0 Hz), 6.82 (2H, d, J=7.6 Hz), 7.18(2H, d, J=8.4 Hz), 7.64 (2H, d, J=8.4 Hz), 7.75 (2H, d, J=7.6 Hz), 7.98(1H, s), 8.54 (1H, s), 10.51 (1H, s) (+)ESI-MS(m/z): 419(M+H)⁺,441(M+Na)⁺

EXAMPLE 129

[1008] The following compound was obtained in substantially the samemanner as in Example 120.

[1009]6-Methyl-2-(4-methyl-1-piperidinyl)-N-{6-[2-(1H-pyrazol-1-yl)ethoxy]-3-pyridinyl}nicotinamide

[1010]¹H-NMR(DMSO-d₆):δ 0.88 (3H, d, J=6.2 Hz), 1.02-1.08 (2H, m),1.40-1.65 (3H, m), 2.39 (3H, s), 2.75-2.87 (2H, m), 3.65-3.71 (2H, m),4.46-4.62 (4H, m), 6.23-6.25 (1H, m), 6.78-6.84 (2H, m), 7.45 (1H, d,J=1.4 Hz), 7.74 (1H, d, J=7.7 Hz), 7.76 (1H, d, J=2.4 Hz), 8.03 (1H, dd,J=2.6 Hz, 8.9 Hz), 8.49 (1H, d, J=2.6 Hz), 10.49 (1H, s) (+)ESI-MS(m/z):421(M+H)⁺, 443(M+Na)⁺

EXAMPLE 130

[1011] The following compound was obtained in substantially the samemanner as in Example 120.

[1012]4-Methyl-2-(4-methyl-1-piperidinyl)-N-{6-[2-(1H-pyrazol-1-yl)ethoxy]-3-pyridinyl}benzamide

[1013]¹H-NMR(DMSO-d₆):δ 0.94 (3H, d, J=6.2 Hz), 1.02-1.53 (3H, m),1.70-1.76 (2H, m), 2.35 (3H, s), 2.72-2.83 (2H, m), 3.14-3.34 (2H, m),4.46-4.52 (2H, m), 4.56-4.62 (2H, m), 6.23-6.25 (1H, m), 6.83 (1H, d,J=8.8 Hz), 7.04 (1H, d, J=8.0 Hz), 7.16 (1H, s), 7.45 (1H, d, J=1.9 Hz),7.75-7.79 (2H, m), 8.08 (1H, dd, J=2.6 Hz, 8.84 Hz), 8.49 (2H, d, J=2.5Hz), 11.79 (1H, s) (+)ESI-MS(m/z): 420(M+H)⁺, 442(M+Na)⁺

EXAMPLE 131

[1014] The following compound was obtained in substantially the samemanner as in Example 120.

[1015]6-Methyl-2-(4-methyl-1-piperidinyl)-N-{4-[2-(1H-pyrrol-1-yl)ethoxy]phenyl}nicotinamide

[1016]¹H-NMR(DMSO-d₆):δ 0.88 (3H, d, J=6.2 Hz), 1.14-1.27 (2H, m),1.45-1.64 (3H, m), 2.39 (3H, s), 2.74-2.85 (2H, m), 3.62-3.68 (2H, m),4.15-4.28 (4H, m), 5.98-6.00 (2H, m), 6.79-6.95 (5H, m), 7.62 (2H, d,J=9.0 Hz), 7.73 (1H, d, J=7.6 Hz), 10.41 (1H, s) (+)ESI-MS(m/z):419(M+H)⁺, 441(M+Na)⁺

EXAMPLE 132

[1017] To a solution of 4-methyl-2-(4-methyl-1-piperidinyl)benzoic acid(117 mg), tert-butyl4-aminophenyl(2-{2-[(tert-butoxycarbonyl)amino]-1,3-thiazol-4-yl)ethyl)carbamate(218 mg) and 1-hydroxybenzotriazole (99 mg) in N,N-dimethylformamide (10ml) was added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimidehydrochloride (WSC.HCl) (124 mg), followed by triethylamine (66 mg) atambient temperature and the mixture was stirred at ambient temperaturefor 3 days. The reaction mixture was poured into a mixture of ethylacetate and water. The organic layer was washed with water and brine,dried over magnesium sulfate and concentrated in vacuo. The residue waspurified by column chromatography on silica gel eluting with hexane:ethyl acetate (3:1 v/v) to give tert-butyl2-{2-[(tert-butoxycarbonyl)amino]-1,3-thiazol-4-yl)ethyl(4-{[4-methyl-2-(4-methyl-1-piperidinyl)benzoyl]amino}phenyl)carbamate(138 mg) as a yellow tar.

[1018]¹H-NMR(DMSO-d₆):δ 1.06(3H, d, J=5.9 Hz), 1.32-1.72(3H, m),1.49(18H, s), 1.86(2H, d, J=9.2 Hz), 2.39(3H, s), 2.84(2H, t, J=11.9Hz), 2.97(2H, t, J=7.8 Hz), 3.18(2H, d, J=11.9 Hz), 3.92(2H, t, J=7.8Hz), 6.79(1H, s), 7.08-7.18(4H, m), 7.73(2H, d, J=8.6 Hz), 8.18(1H, d,J=8.6 Hz), 12.63(1H, s) (+)ESI-MS(m/z): 650(M+H)⁺

EXAMPLE 133

[1019] To a solution of tert-butyl2-{2-[(tert-butoxycarbonyl)amino]-1,3-thiazol-4-yl)ethyl(4-{[4-methyl-2-(4-methyl-1-piperidinyl)benzoyl]amino}phenyl)carbamate(135 mg) in dichloromethane (5 ml) was added trifluoroacetic acid (474mg). The reaction mixture was stirred at ambient temperature for 12hours, quenched with a 10% aqueous potassium carbonate solution, andextracted with dichloromethane. The organic layer was washed with brine,dried over magnesium sulfate, filtered and concentrated in vacuo. Theresidue was triturated with diisopropyl ether to giveN-(4-{[2-(2-amino-1,3-thiazol-4-yl)ethyl]amino}phenyl)-4-methyl-2-(4-methyl-1-piperidinyl)benzamide(68 mg) as a pale brown solid.

[1020]¹H-NMR(DMSO-d₆):δ 0.97(3H, d, J=6.3 Hz), 1.28-1.43(2H, m),1.44-1.62(1H, m), 1.75(2H, d, J=10.9 Hz), 2.33(3H, s), 2.66(2H, t, J=7.3Hz), 2.78(2H, t, J=10.8 Hz), 3.09(2H, d, J=11.6 Hz), 3.24(2H, t, J=7.3Hz), 5.57(1H, brs), 6.23(1H, s), 6.59(2H, d, J=8.6 Hz), 6.88(2H, brs),7.03(1H, d, J=7.6 Hz), 7.16(1H, s), 7.47(2H, d, J=8.9 Hz), 7.82(1H, d,J=7.9 Hz), 11.70(1H, s) (+)ESI-MS(m/z): 450(M+H)⁺

EXAMPLE 134

[1021] The following compound was obtained in substantially the samemanner as in Example 132.

[1022] tert-Butyl2-{2-[(tert-butoxycarbonyl)amino]-1,3-thiazol-4-yl}ethyl(4-{[2-(dimethylamino)-4-methylbenzoyl]amino}phenyl)carbamate

[1023]¹H-NMR(CDCl₃):δ 1.49(18H, s), 2.40(3H, s), 2.82(6H, s), 2.96(2H,t, J=7.6 Hz), 3.92(2H, t, J=7.6 Hz), 6.79(1H, brs), 7.07-7.16(4H, m),7.63(2H, d, J=8.9 Hz), 8.16(1H, d, J=8.9 Hz), 12.28(1H, brs)(+)ESI-MS(m/z): 596(M+H)⁺, 618(M+Na)⁺

EXAMPLE 135

[1024] The following compound was obtained in substantially the samemanner as in Example 133.

[1025]N-(4-{[2-(2-Amino-1,3-thiazol-4-yl)ethyl]amino}phenyl)-2-(dimethylamino)-4-methylbenzamide

[1026]¹H-NMR(DMSO-d₆):δ 2.33(3H, s), 2.66(2H, t, J=7.3 Hz), 2.75(6H, s),3.19-3.30(2H, m), 5.49(1H, brs), 6.22(1H, s), 6.56(2H, d, J=8.9 Hz),6.87(2H, brs), 6.94(1H, d, J=7.9 Hz), 7.08(1H, s), 7.42(2H, d, J=8.9Hz), 7.66(1H, d, J=7.9 Hz), 11.17(1H, s) (+)ESI-MS(m/z): 396(M+H)⁺,418(M+Na)⁺

EXAMPLE 136

[1027] To a solution of 4-methyl-2-(4-methyl-1-piperidinyl)benzoic acid(323 mg), tert-butyl6-{2-[(4-aminophenyl)amino]ethyl}-2-pyridinylcarbamate (454 mg) and1-hydroxybenzotriazole (276 mg) in N,N-dimethylformamide (10 ml) wasadded 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride(WSC.HCl) (345 mg), followed by triethylamine (182 mg) at ambienttemperature and the mixture was stirred at ambient temperature for 11hours. The reaction mixture was poured into a mixture of ethyl acetateand water. The organic layer was washed with water and brine, dried overmagnesium sulfate and concentrated in vacuo. The residue was purified bycolumn chromatography on silica gel eluting with hexane: ethyl acetate(2:1 v/v) to give tert-butyl6-{2-[(4-{[4-methyl-2-(4-methyl-1-piperidinyl)benzoyl]amino}phenyl)amino]-ethyl}-2-pyridinylcarbamate(226 mg) as a pale yellow foam.

[1028]¹H-NMR(CDCl₃):δ 1.03(3H, d, J=6.3 Hz), 1.44-1.54(3H, m), 1.53(9H,s), 1.84(2H, d, J=12.5 Hz), 2.38(3H, s), 2.81(2H, t, J=11.5 Hz),2.96(2H, t, J=6.6 Hz), 3.18(2H, d, J=11.9 Hz), 3.49(2H, t, J=6.6 Hz),6.65(2H, d, J=8.6 Hz), 6.83(1H, d, J=7.3 Hz), 7.06(2H, brs), 7.21(1H,brs), 7.55-7.61(3H, m), 7.76(1H, d, J=8.2 Hz), 8.17(1H, d, J=8.6 Hz),12.25(1H, s) (+)ESI-MS(m/z): 544(M+H)⁺, 566(M+Na)⁺

EXAMPLE 137

[1029] To a solution of tert-butyl6-{2-[(4-{[4-methyl-2-(4-methyl-1-piperidinyl)benzoyl]amino}phenyl)amino]ethyl}-2-pyridinylcarbamate(220 mg) in dichloromethane (10 ml) was added trifluoroacetic acid (692mg). The reaction mixture was stirred at ambient temperature for 16hours, quenched with a 10% aqueous potassium carbonate solution, andextracted with dichloromethane. The organic layer was washed with brine,dried over magnesium sulfate and concentrated in vacuo. The residue wasrecrystallized from ethyl acetate and hexane to giveN-(4-{[2-(6-amino-2-pyridinyl)ethyl]amino}phenyl)-4-methyl-2-(4-methyl-1-piperidinyl)benzamide(120 mg) as a pale yellow solid.

[1030]¹H-NMR(CDCl₃):δ 1.03(3H, d, J=6.3 Hz), 1.40-1.60(3H, m), 2.38(3H,s), 2.81(2H, t, J=11.5 Hz), 2.91(2H, t, J=6.6 Hz), 3.17(2H, d, J=11.9Hz), 3.47(2H, t, J=6.6 Hz), 4.45(2H, brs), 6.36(1H, d, J=8.3 Hz),6.53(1H, d, J=7.3 Hz), 6.65(2H, d, J=8.9 Hz), 7.04-7.08(2H, m), 7.36(1H, t, J=7.3 Hz), 7.57(2H, d, J=8.9 Hz), 8.17(1H, d, J=8.6 Hz),12.24(1H, s) (+)ESI-MS(m/z): 444(M+H)⁺

EXAMPLE 138

[1031] The following compound was obtained in substantially the samemanner as in Example 132.

[1032] tert-Butyl6-{2-[(4-{[2-(dimethylamino)-4-methylbenzoyl]amino}phenyl)amino]ethyl}-2-pyridinylcarbamate

[1033]¹H-NMR(CDCl₃):δ 1.53(9H, s), 2.39(3H, s), 2.80(6H, s), 2.96(2H, t,J=6.6 Hz), 3.49(2H, t, J=6.6 Hz), 6.64(2H, d, J=8.9 Hz), 6.83(1H, d,J=7.3 Hz), 7.04-7.08(2H, m), 7.21(1H, brs), 7.49(2H, d, J=8.6 Hz),7.58(1H, t, J=8.6 Hz), 7.77(1H, d, J=8.3 Hz), 8.14(1H, d, J=8.6 Hz),11.86(1H, s), (+)ESI-MS(m/z): 512(M+Na)⁺

EXAMPLE 139

[1034] The following compound was obtained in substantially the samemanner as in Example 133.

[1035]N-(4-{[2-(6-Amino-2-pyridinyl)ethyl]amino}phenyl)-2-(dimethylamino)-4-methylbenzamide

[1036]¹H-NMR(CDCl₃):δ 2.39(3H, s), 2.80(6H, s), 2.90(2H, t, J=6.6 Hz),3.47(2H, t, J=6.6 Hz), 4.46(2H, brs), 6.36(1H, d, J=7.9 Hz), 6.53(1H, d,J=7.3 Hz), 6.64(2H, d, J=8.9 Hz), 7.04-7.07(2H, m), 7.36(1H, t, J=7.3Hz), 7.48(2H, d, J=8.9 Hz), 8.14(1H, d, J=8.6 Hz), 11.84(1H, s),(+)ESI-MS(m/z): 390(M+H)⁺

[1037] Preparation 108

[1038] To a solution of tert-butyl4-aminophenyl(2-{6-[(tert-butoxycarbonyl)amino]-2-pyridinyl}ethyl)carbamate(578 mg), 2-chloro-6-methylnicotinic acid (769 mg) and1-hydroxybenzotriazole (719 mg) in N,N-dimethylformamide (30 ml) wasadded 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride(WSC.HCl) (901 mg), followed by 4-(dimethylamino)pyridine (49 mg) atambient temperature. The reaction mixture was stirred at the sametemperature for 21 hours and concentrated in vacuo. The residue wasdissolved in ethyl acetate and water, and extracted with ethyl acetate.The organic layer was washed with water and brine, dried over magnesiumsulfate, filtered and concentrated in vacuo. The residue was purified bycolumn chromatography on silica gel eluting with hexane: ethyl acetate(2:1→3:2 v/v) to give tert-butyl2-{6-[(tert-butoxycarbonyl)amino]-2-pyridinyl}ethyl(4-{[(2-chloro-6-methyl-3-pyridinyl)carbonyl]amino}phenyl)carbamate(2.246 g) as a yellow foam.

[1039]¹H-NMR(CDCl₃):δ 1.42(18H, s), 2.60(3H, s), 3.04(2H, t, J=7.7 Hz),3.95(2H, t, J=7.7 Hz), 7.05-7.26(5H, m), 7.57-7.61(3H, m), 8.10(1H, d,J=7.6 Hz), 8.34(1H, s), (+)ESI-MS(m/z): 583(M+H)⁺

EXAMPLE 140

[1040] To a solution of tert-butyl2-{6-[(tert-butoxycarbonyl)amino]-2-pyridinyl)ethyl(4-{[(2-chloro-6-methyl-3-pyridinyl)carbonyl]amino}phenyl)carbamate(681 mg) in tetrahydrofuran (30 ml) was added 4-methylpyperidine (1.16g) at ambient temperature. The reaction mixture was refluxed for 24hours, cooled to ambient temperature, and extracted with ethyl acetate.The organic layer was washed with water and brine, dried over magnesiumsulfate, filtered and concentrated in vacuo. The residue was purified bycolumn chromatography on silica gel eluting with hexane: ethyl acetate(2:1→3:2 v/v) to give tert-butyl2-{6-[(tert-butoxycarbonyl)amino]-2-pyridinyl}ethyl[4-({[6-methyl-2-(4-methyl-1-piperidinyl)-3-pyridinyl]carbonyl}amino)phenyl]carbamate(640 mg) as a yellow foam.

[1041]¹H-NMR(CDCl₃):δ 1.04(3H, d, J=6.3 Hz), 1.32-1.47(2H, m), 1.40(9H,s), 1.49(9H, s), 1.50-1.72(1H, m), 1.85(2H, d, J=10.8 Hz), 2.52(3H, s),2.88-3.05(4H, m), 3.34(2H, d, J=12.5 Hz), 3.95(2H, t, J=7.6 Hz),6.81(1H, d, J=7.2 Hz), 7.03(1H, d, J=7.9 Hz), 7.10-7.17(3H, m), 7.54(1H,t, J=7.7 Hz), 7.67-7.73(3H, m), 8.37(1H, d, J=7.9 Hz), 11.87(1H, s)(+)ESI-MS(m/z): 645(M+H)⁺

EXAMPLE 141

[1042] To a solution of tert-butyl2-{6-[(tert-butoxycarbonyl)amino]-2-pyridinyl}ethyl[4-({[6-methyl-2-(4-methyl-1-piperidinyl)-3-pyridinyl]carbonyl}amino)phenyl]-carbamate(629 mg) in dichloromethane (10 ml) was added trifluoroacetic acid (1.5ml). The reaction mixture was stirred at ambient temperature for 20hours, quenched with a 10% aqueous potassium carbonate solution, andextracted with dichloromethane. The organic layer was washed with brine,dried over magnesium sulfate, filtered and concentrated in vacuo. Theresidue was recrystallized from ethyl acetate-diisopropyl ether to giveN-(4-{[2-(6-amino-2-pyridinyl)ethyl]amino}phenyl)-6-methyl-2-(4-methyl-1-piperidinyl)nicotinamide(294 mg) as a pale brown solid.

[1043]¹H-NMR(DMSO-d₆):δ 0.90(3H, d, J=6.6 Hz), 1.14-1.27(2H, m),1.32-1.59(1H, m), 1.63(2H, d, J=12.5 Hz), 2.38(3H, s), 2.70-2.84(4H, m),3.26(2H, t, J=6.2 Hz), 3.63(2H, d, J=12.8 Hz), 5.56(1H, t, J=5.1 Hz),5.84(2H, s), 6.27(1H, d, J=8.2 Hz), 6.39(1H, d, J=7.2 Hz), 6.57(2H, d,J=9.4 Hz), 6.82(1H, d, J=7.9 Hz), 7.27(1H, t, J=7.7 Hz), 7.42(2H, d,J=8.6 Hz), 7.75(1H, d, J=7.5 Hz), 10.25(1H, s) (+)ESI-MS(m/z): 445(M+H)⁺

EXAMPLE 142

[1044] To a solution of tert-butyl2-{6-[(tert-butoxycarbonyl)amino]-2-pyridinyl}ethyl(4-{[(2-chloro-6-methyl-3-pyridinyl)carbonyl]amino}phenyl)carbamate(681 mg) in tetrahydrofuran (30 ml) was added 2.0 mol/l dimethylamine intetrahydrofuran (6.6 ml) at ambient temperature. The reaction mixturewas heated at 60° C. for 20 hours, cooled to ambient temperature, andextracted with ethyl acetate. The organic layer was washed with waterand brine, dried over magnesium sulfate, filtered and concentrated invacuo. The residue was purified by column chromatography on silica geleluting with hexane: ethyl acetate (2:1→3:2 v/v) to give tert-butyl2-{6-[(tert-butoxycarbonyl)amino]-2-pyridinyl}ethyl[4-({[2-(dimethylamino)-6-methyl-3-pyridinyl]carbonyl)amino)phenyl]-carbamate(529 mg) as a yellow foam.

[1045]¹H-NMR(CDCl₃):δ 1.40(9H, s), 1.50(9H, s), 2.52 (3H, s), 2.90(6H,s), 2.91(2H, t, J=7.4 Hz), 3.95(2H, t, J=7.4 Hz), 6.81(1H, d, J=7.6 Hz),6.97(1H, d, J=7.9 Hz), 7.12-7.16(3H, m), 7.54(1H, t, J=7.9 Hz), 7.62(2H,d, J=8.6 Hz), 7.72(1H, d, J=8.2 Hz), 8.27(1H, d, J=7.9 Hz), 10.90(1H, s)(+)ESI-MS(m/z): 645(M+H)⁺

EXAMPLE 143

[1046] The following compound was obtained in substantially the samemanner as in Example 141.

[1047]N-(4-{[2-(6-Amino-2-pyridinyl)ethyl]amino}phenyl)-2-(dimethylamino)-6-methylnicotinamide

[1048]¹H-NMR(DMSO-d₆):δ 2.34(3H, s), 2.72(2H, t, J=7.2 Hz), 2.94(6H, s),3.26(2H, t, J=7.2 Hz), 5.54(1H, s), 5.84(2H, s), 6.27(1H, d, J=8.2 Hz),6.40(1H, d, J=7.2 Hz), 6.55(2H, d, J=8.9 Hz), 6.59(1H, d, J=7.6 Hz),7.27(1H, t, J=7.7 Hz), 7.39(2H, d, J=8.9 Hz), 7.54(1H, d, J=7.2 Hz),9.91(1H, s) (+)ESI-MS(m/z): 391(M+H)⁺

[1049] Preparation 109

[1050] The following compound was obtained in substantially the samemanner as in Preparation 108.

[1051] tert-Butyl6-[2-(4-{[(2-chloro-6-methyl-3-pyridinyl)carbonyl]amino}phenoxy)ethyl]-2-pyridinylcarbamate

[1052]¹H-NMR(CDCl₃):δ 1.51(9H, s), 2.59(3H, s), 3.13(2H, t, J=6.7 Hz),4.31(2H, t, J=6.7 Hz), 6.90(2H, d, J=9.2 Hz), 7.21(1H, d, J=7.2 Hz),7.22(1H, s), 7.50-7.61(3H, m), 7.77(1H, d, J=8.2 Hz), 8.12(1H, d, J=7.9Hz), 8.19(1H, s) (+)ESI-MS(m/z): 483(M+H)⁺

EXAMPLE 144

[1053] The following compound was obtained in substantially the samemanner as in Example 140.

[1054] tert-Butyl6-{2-[4-({[6-methyl-2-(4-methyl-1-piperidinyl)-3-pyridinyl]carbonyl}amino)phenoxy]ethyl}-2-pyridinylcarbamate

[1055]¹H-NMR(CDCl₃):δ 1.02(3H, d, J=6.6 Hz), 1.36-1.47(2H, m), 1.51(9H,s), 1.52-1.65(1H, m), 1.83(2H, d, J=10.5 Hz), 2.51(3H, s), 2.99(2H, td,J=12.2,2.3 Hz), 3.12(1H, t, J=6.7 Hz), 3.34(2H, d, J=12.8 Hz), 4.31(2H,t, J=6.9 Hz), 6.91(2H, d, J=8.9 Hz), 7.01(1H, d, J=7.2 Hz), 7.18(1H, s),7.59(1H, t, J=2.9 Hz), 7.63(2H, d, J=8.9 Hz), 7.76(1H, d, J=7.9 Hz),8.35(1H, d, J=7.9 Hz), 11.63(1H, s) (+)ESI-MS(m/z): 546(M+H)⁺

EXAMPLE 145

[1056] The following compound was obtained in substantially the samemanner as in Example 141.

[1057]N-{4-[2-(6-Amino-2-pyridinyl)ethoxy]phenyl}-6-methyl-2-(4-methyl-1-piperidinyl)nicotinamide

[1058]¹H-NMR(DMSO-d₆):δ 0.88(3H, d, J=6.3 Hz), 1.11-1.26(2H, m),1.46-1.51(1H, m), 1.62(2H, d, J=12.5 Hz), 2.38(3H, s), 2.80(2H, t,J=10.7 Hz), 2.92(2H, t, J=6.7 Hz), 3.65(2H, d, J=12.8 Hz), 4.24(2H, t,J=6.7 Hz), 5.83(1H, s), 6.28(1H, d, J=7.6 Hz), 6.44(1H, d, J=6.9 Hz),6.81(1H, d, J=7.6 Hz), 6.91(2H, d, J=8.9 Hz), 7.28(1H, dd, J=8.2 Hz, 7.2Hz), 7.61(2H, d, J=9.2 Hz), 7.74(1H, d, J=7.6 Hz), 10.39(1H, s),(+)ESI-MS(m/z): 446(M+H)⁺

EXAMPLE 146

[1059] The following compound was obtained in substantially the samemanner as in Example 142.

[1060] tert-Butyl6-{2-[4-({[2-(dimethylamino)-6-methyl-3-pyridinyl]carbonyl}amino)phenoxy]ethyl}-2-pyridinylcarbamate

[1061]¹H-NMR(CDCl₃):δ 1.51(9H, s), 2.50(3H, s), 2.88(6H, s), 3.12(2H, t,J=6.7 Hz), 4.30(2H, t, J=6.7 Hz), 6.87-6.95(4H, m), 7.20(1H, br s),7.54(2H, d, J=9.2 Hz), 7.57(1H, d, J=7.9 Hz), 7.77(1H, d, J=7.9 Hz),8.24(1H, d, J=7.6 Hz), 10.64(1H, s), (+)ESI-MS(m/z): 514(M+Na)⁺

EXAMPLE 147

[1062] The following compound was obtained in substantially the samemanner as in Example 141.

[1063]N-{4-[2-(6-Amino-2-pyridinyl)ethoxy]phenyl}-2-(dimethylamino)-6-methylnicotinamide

[1064]¹H-NMR(DMSO-d₆):δ 2.35(3H, s), 2.93(6H, s), 2.97(2H, t, J=6.9 Hz),4.24(2H, t, J=6.7 Hz), 6.35(2H, br s), 6.43(1H, d, J=8.2 Hz), 6.54(1H,d, J=7.2 Hz), 6.60(1H, d, J=7.6 Hz), 6.89(2H, d, J=8.9 Hz), 7.43(1H, t,J=7.7 Hz), 7.57(1H, d, J=7.6 Hz), 7.58(2H, d, J=8.9 Hz), 10.14(1H, s)(+)ESI-MS(m/z): 392(M+H)⁺

[1065] Preparation 110

[1066] The following compound was obtained in substantially the samemanner as in Preparation 108.

[1067] tert-Butyl2-{2-[(tert-butoxycarbonyl)amino]-1,3-thiazol-4-yl}ethyl(4-{[(2-chloro-6-methyl-3-pyridinyl)carbonyl]amino}phenyl)carbamate

[1068]¹H-NMR(CDCl₃):δ 1.49(18H, s), 2.60(3H, s), 2.94(2H, t, J=7.6 Hz),3.91(2H, t, J=7.6 Hz), 6.77(1H, s), 7.15(2H, d, J=8.6 Hz), 7.24(1H, d,J=7.9 Hz), 7.59(2H, d, J=8.9 Hz), 8.11(1H, d, J=7.9 Hz), 8.32(1H, s)(+)ESI-MS(m/z): 610(M+Na)⁺

EXAMPLE 148

[1069] The following compound was obtained in substantially the samemanner as in Example 140.

[1070] tert-Butyl2-{2-[(tert-butoxycarbonyl)amino]-1,3-thiazol-4-yl}ethyl[4-({[6-methyl-2-(4-methyl-1-piperidinyl)-3-pyridinyl]carbonyl}amino)phenyl]carbamate

[1071]¹H-NMR(CDCl₃):δ 1.03(3H, d, J=6.6 Hz), 1.40(9H, s), 1.51(9H, s),1.45-1.73(3H, m), 1.82-1.87(2H, m), 2.52(3H, s), 2.88(2H, t, J=7.6 Hz),3.00(2H, t, J=11.3 Hz), 3.34(2H, d, J=12.5 Hz), 3.92(2H, t, J=7.6 Hz),6.52(1H, s), 7.02(1H, d, J=7.9 Hz), 7.15(2H, d, J=7.9 Hz), 7.68(2H, d,J=8.6 Hz), 8.36(1H, d, J=7.9 Hz), 8.39(1H, s), 11.85(1H, s)(+)ESI-MS(m/z): 651(M+H)⁺

EXAMPLE 149

[1072] The following compound was obtained in substantially the samemanner as in Example 141.

[1073]N-(4-{[2-(2-Amino-1,3-thiazol-4-yl)ethyl]amino}phenyl)-6-methyl-2-(4-methyl-1-piperidinyl)nicotinamide

[1074]¹H-NMR(DMSO-d₆):δ 0.90(3H, d, J=6.3 Hz), 1.11-1.28(2H, m),1.44-1.6(1H, m), 1.63(2H, d, J=12.2 Hz), 2.38(3H, s), 2.65(2H, t, J=7.2Hz), 2.79(2H, t, J=12.2 Hz), 3.23(2H, dd, J=7.2 Hz, 5.6 Hz), 3.63(2H, d,J=12.5 Hz), 5.49(1H, t, J=5.6 Hz), 6.21(1H, s), 6.54(2H, d, J=8.6 Hz),6.82(1H, d, J=7.6 Hz), 6.85(2H, s), 7.43(2H, d, J=8.6 Hz), 7.74(1H, d,J=7.6 Hz), 10.26(1H, s) (+)ESI-MS(m/z): 451(M+H)⁺

EXAMPLE 150

[1075] The following compound was obtained in substantially the samemanner as in Example 142.

[1076] tert-Butyl2-{2-[(tert-butoxycarbonyl)amino]-1,3-thiazol-4-yl}ethyl[4-({[2-(dimethylamino)-6-methyl-3-pyridinyl]carbonyl}amino)phenyl]carbamate

[1077]¹H-NMR(CDCl₃):δ 1.40(9H, s), 1.50(9H, s), 2.51(3H, s), 2.89(6H,s), 2.90(2H, t, J=7.6 Hz), 3.91(2H, t, J=7.6 Hz), 6.52(1H, s), 6.96(1H,d, J=7.9 Hz), 7.12(2H, d, J=8.2 Hz), 7.60(2H, d, J=8.6 Hz), 8.25(1H, d,J=7.9 Hz), 8.66(1H, br s), 10.88(1H, s) (+)ESI-MS(m/z): 597(M+H)⁺

EXAMPLE 151

[1078] The following compound was obtained in substantially the samemanner as in Example 141.

[1079]N-(4-{[2-(2-Amino-1,3-thiazol-4-yl)ethyl]amino}phenyl)-2-(dimethylamino)-6-methylnicotinamide

[1080]¹H-NMR(DMSO-d₆):δ 2.34(3H, s), 2.65(2H, t, J=7.4 Hz), 2.93(6H, s),3.22(2H, dd, J=7.4 Hz, 5.6 Hz), 5.46(1H, t, J=5.6 Hz), 6.20(1H, s),6.53(2H, d, J=8.6 Hz), 6.59(1H, d, J=7.2 Hz), 6.84(2H, s), 7.39(2H, d,J=8.6 Hz), 7.53(1H, d, J=7.6 Hz), 9.90(1H, s), (+)ESI-MS(m/z): 397(M+H)⁺

[1081] Preparation 111

[1082] The following compound was obtained in substantially the samemanner as in Preparation 108.

[1083] tert-Butyl4-[2-(4-{[(2-chloro-6-methyl-3-pyridinyl)carbonyl]amino}phenoxy)ethyl]-1,3-thiazol-2-ylcarbamate

[1084]¹H-NMR(CDCl₃):δ 1.53(9H, s), 2.59(3H, s), 3.13(2H, t, J=6.5 Hz),4.24(2H, t, J=6.8 Hz), 6.62(1H, s), 6.90(2H, d, J=9.2 Hz), 7.21(1H, d,J=7.9 Hz), 7.50(2H, d, J=8.9 Hz), 8.11(1H, d, J=7.6 Hz), 8.19(1H, s)(+)ESI-MS(m/z): 489(M+H)⁺

EXAMPLE 152

[1085] The following compound was obtained in substantially the samemanner as in Example 140.

[1086] tert-Butyl4-{2-[4-({[6-methyl-2-(4-methyl-1-piperidinyl)-3-pyridinyl]carbonyl}amino)phenoxy]ethyl}-1,3-thiazol-2-ylcarbamate

[1087]¹H-NMR(CDCl₃):δ 1.01(3H, d, J=6.3 Hz), 1.30-1.47(2H, m), 1.53(9H,s), 1.54-1.97(1H, m), 1.83(2H, d, J=12.8 Hz), 2.51(3H, s), 2.98(2H, t,J=10.8 Hz), 3.17(2H, t, J=6.6 Hz), 3.34(2H, d, J=12.5 Hz), 4.25(2H, t,J=6.6 Hz), 6.64(1H, s), 6.91(2H, d, J=8.9 Hz), 7.01(1H, d, J=7.9 Hz),7.64(2H, d, J=9.2 Hz), 8.35(1H, d, J=7.9 Hz), 9.55(1H, br s), 11.63(1H,s) (+)ESI-MS(m/z): 552(M+H)⁺

EXAMPLE 153

[1088] The following compound was obtained in substantially the samemanner as in Example 141.

[1089]N-{4-[2-(2-Amino-1,3-thiazol-4-yl)ethoxy]phenyl}-6-methyl-2-(4-methyl-1-piperidinyl)nicotinamide

[1090]¹H-NMR(DMSO-d₆):δ 0.89(3H, d, J=6.3 Hz), 1.11-1.25(2H, m),1.44-1.52(1H, m), 1.62(2H, d, J=12.5 Hz), 2.38(3H, s), 2.76-2.87(4H, m),3.65(2H, d, J=12.8 Hz), 4.17(2H, t, J=6.9 Hz), 6.26(1H, s), 6.81(1H, d,J=7.6 Hz), 6.86(2H, s), 6.92(2H, d, J=8.9 Hz), 7.62(2H, d, J=8.9 Hz),7.74(1H, d, J=7.6 Hz), 10.39(1H, s) (+)ESI-MS(m/z): 452(M+H)⁺

EXAMPLE 154

[1091] The following compound was obtained in substantially the samemanner as in Example 142.

[1092] tert-Butyl4-{2-[4-({[2-(dimethylamino)-6-methyl-3-pyridinyl]carbonyl}amino)phenoxy]ethyl}-1,3-thiazol-2-ylcarbamate

[1093]¹H-NMR(CDCl₃):δ 1.53(9H, s), 2.51(3H, s), 2.89(6H, s), 3.14(2H, t,J=6.7 Hz), 4.24(2H, t, J=6.7 Hz), 6.63(1H, s), 6.89(2H, d, J=9.2 Hz),6.94(1H, d, J=7.9 Hz), 7.55(2H, d, J=9.2 Hz), 8.24(1H, d, J=7.9 Hz),9.02(1H, br s), 10.66(1H, s) (+)ESI-MS(m/z): 498(M+H)⁺

EXAMPLE 155

[1094] The following compound was obtained in substantially the samemanner as in Example 141.

[1095]N-{4-[2-(2-Amino-1,3-thiazol-4-yl)ethoxy]phenyl}-2-(dimethylamino)-6-methylnicotinamide

[1096]¹H-NMR(DMSO-d₆):δ 2.35(3H, s), 2.84(2H, t, J=6.7 Hz), 2.93(6H, s),4.16(2H, t, J=6.7 Hz), 6.26(1H, s), 6.60(1H, d, J=7.6 Hz), 6.86(2H, s),6.89(2H, d, J=8.9 Hz), 7.56(1H, d, J=7.2 Hz), 7.58(2H, d, J=8.9 Hz),10.14(1H, s) (+)ESI-MS(m/z): 398(M+H)⁺

EXAMPLE 156

[1097] To a solution of tert-butyl4-[2-(4-aminophenoxy)ethyl]-1,3-thiazol-2-ylcarbamate (177 mg),4-methyl-2-(4-methyl-1-piperidinyl)benzoic acid (135 mg) and1-hydroxybenzotriazole (88.9 mg) in N,N-dimethylformamide (3.5 ml) wasadded 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride(WSC.HCl) (111 mg), followed by N,N-dimethylaminopyridine (3.2 mg) atambient temperature. The reaction mixture was stirred at ambienttemperature for 23 hours and concentrated in vacuo. The residue wasdissolved in ethyl acetate and water, and extracted with ethyl acetate.The organic layer was washed with water and brine, dried over magnesiumsulfate, filtered and concentrated in vacuo. The residue was purified bycolumn chromatography on silica gel eluting with hexane: ethyl acetate(2:1→1:1 v/v) to give tert-butyl4-[2-(4-{[4-methyl-2-(4-methyl-1-piperidinyl)benzoyl]amino}phenoxy)ethyl]-1,3-thiazol-2-ylcarbamate(0.159 g) as a pale brown foam.

[1098]¹H-NMR(DMSO-d₆):δ 1.03(3H, d, J=6.2 Hz), 1.40-1.70(1H, m),1.47(2H, td, J=13.2, 3.5 Hz), 1.54(9H, s), 1.84(2H, dd, J=13.0 Hz, 1.6Hz), 2.38(3H, s), 2.82(2H, t, J=11.3 Hz), 3.10-3.21(4H, m), 4.23(2H, d,J=6.8 Hz), 6.64(1H, s), 6.89(2H, d, J=9.2 Hz), 7.06(1H, d, J=7.3 Hz),7.08(1H, s), 7.65(2H, d, J=9.2 Hz), 8.16(1H, d, J=8.1 Hz), 12.44(1H, s)(+)ESI-MS(m/z): 551(M+H)⁺

EXAMPLE 157

[1099] To a solution of tert-butyl4-[2-(4-{[4-methyl-2-(4-methyl-1-piperidinyl)benzoyl]amino}phenoxy)ethyl]-1,3-thiazol-2-ylcarbamate(159 mg) in dichloromethane (1.58 ml) was added trifluoroacetic acid(0.334 ml). The mixture was stirred for 12 hours at room temperature,quenched with 10% aqueous potassium carbonate solution, and extractedwith dichloromethane. The organic layer was washed with brine, driedover magnesium sulfate, filtered and concentrated in vacuo. The residuewas recrystallized from hexane-ethyl acetate to giveN-{4-[2-(2-amino-1,3-thiazol-4-yl)ethoxy]phenyl)-4-methyl-2-(4-methyl-1-piperidinyl)benzamide(0.059 g) as a pale brown powder.

[1100]¹H-NMR(CDCl₃):δ 1.04(3H, d, J=5.9 Hz), 1.48(2H, td, J=11.3 Hz),1.50-1.70(1H, m), 1.85(2H, dd, J=12.7 Hz, 2.7 Hz), 2.38(3H, s), 2.82(2H,td, J=11.9 Hz, 2.2 Hz), 3.02(2H, t, J=6.8 Hz), 4.25(2H, t, J=6.8 Hz),5.03(1H, br s), 6.28(1H, s), 6.92(2H, d, J=9.2 Hz), 7.06-7.23(2H, m),7.66(2H, d, J=9.2 Hz), 8.17(2H, d, J=8.4 Hz), 12.41(1H, s)(+)ESI-MS(m/z): 451(M+H)⁺

EXAMPLE 158

[1101] The following compound was obtained in substantially the samemanner as in Example 156.

[1102] tert-Butyl4-[2-(4-{[2-(dimethylamino)-4-methylbenzoyl]amino}phenoxy)ethyl]-1,3-thiazol-2-ylcarbamate

[1103]¹H-NMR(CDCl₃):δ 1.55(9H, s), 2.39(3H, s), 2.80(6H, s), 3.13(2H, t,J=6.5 Hz), 4.22(2H, t, J=6.8 Hz), 6.63(1H, s), 6.87(2H, d, J=8.9 Hz),7.06(1H, d, J=8.4 Hz), 7.08(1H, s), 7.55(2H, d, J=8.9 Hz), 8.13(1H, d,J=7.6 Hz), 12.08(1H, s) (+)ESI-MS(m/z): 497(M+H)⁺

EXAMPLE 159

[1104] The following compound was obtained in substantially the samemanner as in Example 157.

[1105]N-{4-[2-(2-Amino-1,3-thiazol-4-yl)ethoxy]phenyl}-2-(dimethylamino)-4-methylbenzamide

[1106]¹H-NMR(CDCl₃):δ 2.39(3H, s), 2.80(6H, s), 3.02(2H, t, J=6.8 Hz),4.24(2H, t, J=6.8 Hz), 4.96(2H, br s), 6.26(1H, s), 6.91(2H, d, J=8.9Hz), 7.07(1H, d, J=7.3 Hz), 7.08(1H, s), 7.57(2H, d, J=9.2 Hz), 8.14(2H,d, J=8.6 Hz), 12.04(1H, s) (+)ESI-MS(m/z): 397(M+H)⁺

EXAMPLE 160

[1107] The following compound was obtained in substantially the samemanner as in Example 156.

[1108] tert-Butyl4-{2-[(5-{[4-methyl-2-(4-methyl-1-piperidinyl)benzoyl]amino}-2-pyridinyl)oxy]ethyl}-1,3-thiazol-2-ylcarbamate

[1109]¹H-NMR(CDCl₃):δ 1.05(3H, d, J=6.2 Hz), 1.46(2H, td, J=13.0, 3.8Hz), 1.54(9H, s), 1.55-1.72(1H, m), 1.87(2H, dd, J=13.5 Hz, 1.6 Hz),2.39(3H, s), 2.84(2H, t, J=9.7 Hz), 3.10-3.19(4H, m), 4.57(2H, t, J=7.0Hz), 6.62(1H, s), 6.76(1H, d, J=10.0 Hz), 7.09(1H, d, J=7.3 Hz),7.11(1H, s), 8.18(1H, d, J=8.6 Hz), 8.27-8.31(2H, m), 12.64(1H, s)(+)ESI-MS(m/z): 552(M+H)⁺

EXAMPLE 161

[1110] The following compound was obtained in substantially the samemanner as in Example 157.

[1111]N-{6-[2-(2-Amino-1,3-thiazol-4-yl)ethoxy]-3-pyridinyl}-4-methyl-2-(4-methyl-1-piperidinyl)benzamide

[1112]¹H-NMR(CDCl₃):δ 1.06(3H, d, J=6.2 Hz), 1.44-1.72(1H, m), 1.46(2H,td, J=11.9, 3.5 Hz), 1.85(2H, dd, J=13.5 Hz, 1.7 Hz), 2.39(3H, s),2.84(2H, td, J=11.6 Hz, 2.2 Hz), 3.04(2H, t, J=6.8 Hz), 3.17(2H, br d,J=12.4 Hz), 4.56(2H, t, J=7.0 Hz), 4.89(1dH, br s), 6.27(1H, s),6.77(1H, d, J=8.6 Hz), 7.10(1H, d, J=7.0 Hz), 7.11(1H, s), 8.18(1H, d,J=8.6 Hz), 8.23-8.33(2H, m), 12.65(1H, s) (+)ESI-MS(m/z): 452(M+H)⁺

EXAMPLE 162

[1113] The following compound was obtained in substantially the samemanner as in Example 156.

[1114] tert-Butyl4-{2-[(5-{[2-(dimethylamino)-4-methylbenzoyl]amino)-2-pyridinyl)oxy]ethyl)-1,3-thiazol-2-ylcarbamate

[1115]¹H-NMR(CDCl₃):δ 1.56(9H, s), 2.40(3H, s), 2.80(6H, s), 3.13(2H, t,J=6.5 Hz), 4.54(2H, t, J=6.8 Hz), 6.62(1H, s), 6.71(1H, d, J=8.9 Hz),7.09(1H, d, J=8.4 Hz), 7.11(1H, s), 8.12-8.21(3H, m), 12.37(1H, br s)(+)ESI-MS(m/z): 498(M+H)⁺

EXAMPLE 163

[1116] The following compound was obtained in substantially the samemanner as in Example 157.

[1117]N-{6-[2-(2-Amino-1,3-thiazol-4-yl)ethoxy]-3-pyridinyl)-2-(dimethylamino)-4-methylbenzamide

[1118]¹H-NMR(CDCl₃):δ 2.40(3H, s), 2.81(6H, s), 3.03(2H, t, J=6.8 Hz),4.56(2H, t, J=6.8 Hz), 4.92(2H, br s), 6.25(1H, s), 6.76(1H, d, J=8.9Hz), 7.10(1H, d, J=8.6 Hz), 7.11(1H, s), 8.13-8.23(3H, m), 12.32(1H, s)(+)ESI-MS(m/z): 398(M+H)⁺

EXAMPLE 164

[1119] To a solution of tert-butyl6-[2-(4-aminophenoxy)ethyl]-2-pyridinylcarbamate (498 mg),4-methyl-2-(4-methyl-1-piperidinyl)benzoic acid (423 mg) and1-hydroxybenzotriazole (278 mg) in N,N-dimethylformamide (30 ml) wasadded 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride(WSC.HCl) (348 mg), followed by 4-(dimethylamino)pyridine (18 mg) atambient temperature. The reaction mixture was stirred at the sametemperature for 21 hours and concentrated in vacuo. The residue wasdissolved in ethyl acetate and water, and extracted with ethyl acetate.The organic layer was washed with water and brine, dried over magnesiumsulfate, filtered and concentrated in vacuo. The residue was purified bycolumn chromatography on silica gel eluting with hexane: ethyl acetate(4:1 v/v) to give tert-butyl6-[2-(4-{[4-methyl-2-(4-methyl-1-piperidinyl)benzoyl]amino}phenoxy)ethyl]-2-pyridinylcarbamate(312 mg) as a yellow foam.

[1120]¹H-NMR(DMSO-d₆):δ 0.95(3H, d, J=6.3 Hz), 1.30-1.35(2H, m),1.45(9H, s), 1.47-1.54(1H, m), 1.73(2H, d, J=11.2 Hz), 2.34(3H, s),2.77(2H, t, J=10.5 Hz), 3.04-3.12(4H, m), 4.30(2H, t, J=6.6 Hz),6.94(2H, d, J=9.2 Hz), 6.98-7.04(2H, m), 7.16(1H, s), 7.62-7.66(14H, m),7.80(1H, d, J=7.9 Hz), 9.65(1H, s), 11.79(1H, s), (+)ESI-MS(m/z):567(M+Na)⁺

EXAMPLE 165

[1121] To a solution of tert-butyl6-[2-(4-{[4-methyl-2-(4-methyl-1-piperidinyl)benzoyl]amino}phenoxy)ethyl]-2-pyridinylcarbamate(302 mg) in dichloromethane (5 ml) was added trifluoroacetic acid (0.854ml). The reaction mixture was stirred at ambient temperature for 19hours, quenched with 10% aqueous potassium carbonate solution, andextracted with dichloromethane. The organic layer was washed with brine,dried over magnesium sulfate, filtered and concentrated in vacuo. Theresidue was recrystallized from ethyl acetate-diisopropyl ether to giveN-{4-[2-(6-amino-2-pyridinyl)ethoxy]phenyl}-4-methyl-2-(4-methyl-1-piperidinyl)benzamide(294 mg) as a white solid.

[1122]¹H-NMR(DMSO-d₆):δ 0.95(3H, d, J=6.3 Hz), 1.25-1.39(2H, m),1.46-1.53(1H, m), 1.73(2H, d, J=10.8 Hz), 2.34(3H, s), 2.77(2H, t,J=10.2 Hz), 2.92(2H, t, J=6.7 Hz), 3.10(2H, d, J=11.5 Hz), 4.24(2H, t,J=6.7 Hz), 5.85(2H, s), 6.29(1H, d, J=8.2 Hz), 6.45(1H, d, J=6.6 Hz),6.94(2H, d, J=8.9 Hz), 7.04(1H, d, J=7.9 Hz), 7.16(1H, s), 7.29(1H, dd,J=8.2 Hz, 7.2 Hz), 7.65(2H, d, J=9.2 Hz), 7.80(1H, d, J=7.6 Hz),11.80(1H, s) (+)ESI-MS(m/z): 445(M+H)⁺

EXAMPLE 166

[1123] The following compound was obtained in substantially the samemanner as in of Example 164.

[1124] tert-Butyl6-[2-(4-{[2-(dimethylamino)-4-methylbenzoyl]amino}phenoxy)ethyl]-2-pyridinylcarbamate

[1125]¹H-NMR(DMSO-d₆):δ 1.46(9H, s), 2.33(3H, s), 2.75(6H, s), 3.06(2H,t, J=6.6 Hz), 4.30(2H, t, J=6.6 Hz), 6.90-6.94(3H, m), 6.99(1H, dd,J=5.9 Hz, 2.6 Hz), 7.07(1H, s), 7.59-7.67(5H, m), 9.65(1H, s), 11.32(1H,s) (+)ESI-MS(m/z): 513(M+Na)⁺

EXAMPLE 167

[1126] The following compound was obtained in substantially the samemanner as in Example 165.

[1127]N-{4-[2-(6-Amino-2-pyridinyl)ethoxy]phenyl}-2-(dimethylamino)-4-methylbenzamide

[1128]¹H-NMR(DMSO-d₆):δ 2.33(3H, s), 2.75(6H, s), 2.92(2H, t, J=6.7 Hz),4.24(2H, t, J=6.7 Hz), 5.85(2H, s), 6.29(1H, d, J=8.2 Hz), 6.45(1H, d,J=7.2 Hz), 6.89-6.94(3H, m), 7.07(1H, s), 7.29(1H, t, J=7.7 Hz),7.59-7.66(3H, m), 11.32(1H, s) (+)ESI-MS(m/z): 391(M+H)⁺

EXAMPLE 168

[1129] To a solution of tert-butyl6-[2-(4-aminophenoxy)ethyl]-2-pyridinylcarbamate (458 mg),2-(dimethylamino)benzoic acid (253 mg) and 1-hydroxybenzotriazole (256mg) in N,N-dimethylformamide (10 ml) was added1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (320 mg),followed by triethylamine (0.29 ml) at ambient temperature. The reactionmixture was stirred at the same temperature for 16 hours andconcentrated in vacuo. The residue was dissolved in ethyl acetate andwater, and extracted with ethyl acetate. The organic layer was washedwith water and brine, dried over magnesium sulfate, filtered andconcentrated in vacuo. The residue was purified by column chromatographyon silica gel eluting with hexane: ethyl acetate (4:1 v/v) to givetert-butyl6-[2-(4-{[2-(dimethylamino)benzoyl]amino}phenoxy)ethyl]-2-pyridinylcarbamate(549 mg) as a pale yellow foam.

[1130]¹H-NMR(CDCl₃):δ 1.51(9H, s), 2.82(6H, s), 3.12(2H, t, J=6.7 Hz),4.31(2H, t, J=6.7 Hz), 6.88-6.92(3H, m), 7.21-7.30(3H, m), 7.43-7.50(1H,m), 7.54-7.64(3H, m), 7.77(1H, d, J=8.2 Hz), 8.25(1H, dd, J=7.9 Hz, 1.6Hz), 11.98(1H, s) (+)ESI-MS(m/z): 477(M+H)⁺

EXAMPLE 169

[1131] The following compound was obtained in substantially the samemanner as in Example 165.

[1132]N-{4-[-2-(6-Amino-2-pyridinyl)ethoxy]phenyl}-2-(dimethylamino)benzamide

[1133]¹H-NMR(DMSO-d₆):δ 2.76(6H, s), 2.92(2H, t, J=6.7 Hz), 4.24(2H, t,J=6.7 Hz), 5.86(1H, s), 6.30(1H, d, J=8.2 Hz), 6.45(1H, d, J=7.2 Hz),6.91(2H, d, J=9.2 Hz), 7.07(1H, td, J=7.2 Hz, 1.0 Hz), 7.20(1H, d, J=7.6Hz), 7.27-7.33(1H, m), 7.42(1H, td, J=7.2 Hz, 1.6 Hz), 7.60-7.68(3H, m),11.07(1H, s) (+)ESI-MS(m/z): 377(M+H)⁺

EXAMPLE 170

[1134] The following compound was obtained in substantially the samemanner as in Example 168.

[1135] tert-Butyl2-(6-[(tert-butoxycarbonyl)amino]-2-pyridinyl}ethyl(4-{[2-(dimethylamino)benzoyl]amino}phenyl)-carbamate

[1136]¹H-NMR(CDCl₃):δ 1.41(18H, s), 2.79(6H, s), 3.04(2H, t, J=6.9 Hz),3.95(2H, t, J=6.9 Hz), 7.06-7.18(4H, m), 7.24-7.30(3H, m), 7.45-7.51(1H,m), 7.58-7.65(3H, m), 8.26(1H, dd, J=7.9 Hz, 1.9 Hz), 12.21(1H, s)(+)ESI-MS(m/z): 576(M+H)⁺

EXAMPLE 171

[1137] The following compound was obtained in substantially the samemanner as in Example 165.

[1138]N-(4-{[2-(6-Amino-2-pyridinyl)ethyl]amino}phenyl)-2-(dimethylamino)benzamide

[1139]¹H-NMR(DMSO-d₆):δ 2.72(2H, t, J=7.3 Hz), 2.76(6H, s), 3.27(2H, t,J=7.3 Hz), 5.55(1H, s), 5.83(2H, s), 6.27(1H, d, J=8.2 Hz), 6.40(1H, d,J=7.2 Hz), 6.58(2H, d, J=8.9 Hz), 7.06(1H, td, J=7.6 Hz, 1.0 Hz),7.21(1H, d, J=7.2 Hz), 7.28(1H, t, J=7.7 Hz), 7.38-7.45(3H, m), 7.68(1H,dd, J=7.6 Hz, 1.6 Hz), 10.93(1H, s) (+)ESI-MS(m/z): 376(M+H)⁺

EXAMPLE 172

[1140] The following compound was obtained in substantially the samemanner as in Example 168.

[1141] tert-Butyl2-{2-[(tert-butoxycarbonyl)amino]-1,3-thiazol-4-yl)ethyl(4-{[2-(dimethylamino)benzoyl]amino}phenyl)carbamate

[1142]¹H-NMR(CDCl₃):δ 1.42(9H, s), 1.49(9H, s), 2.83(6H, s), 2.95(2H, t,J=7.7 Hz), 3.91(2H, t, J=7.7 Hz), 6.78(1H, s), 7.14(2H, d, J=8.6 Hz),7.24-7.32(2H, m), 7.45-7.51(1H, m), 7.63(2H, d, J=8.9 Hz), 8.25(1H, dd,J=7.6 Hz, 1.3 Hz), 12.20(1H, s) (+)ESI-MS(m/z): 582(M+H)⁺

EXAMPLE 173

[1143] The following compound was obtained in substantially the samemanner as in Example 165.

[1144]N-(4-{[2-(2-Amino-1,3-thiazol-4-yl)ethyl]amino}phenyl)-2-(dimethylamino)benzamide

[1145]¹H-NMR(DMSO-d₆):δ 2.66(2H, t, J=7.2 Hz), 2.76(6H, s), 3.23(2H, q,J=7.1 Hz), 5.48(1H, t, J=5.7 Hz), 6.21(1H, s), 6.55(2H, d, J=9.2 Hz),6.85(2H, s), 7.07(1H, td, J=7.6 Hz, 1.0 Hz), 7.20(1H, dd, J=8.2 Hz, 0.6Hz), 7.39(1H, d, J=1.6 Hz), 7.43(2H, d, J=8.9 Hz), 7.68(1H, dd, J=7.6Hz, 1.6 Hz), 10.93(1H, s) (+)ESI-MS(m/z): 382(M+H)⁺

EXAMPLE 174

[1146] The following compound was obtained in substantially the samemanner as in Example 168.

[1147] tert-Butyl4-[2-(4-{[2-(dimethylamino)benzoyl]amino}-phenoxy)ethyl]-1,3-thiazol-2-ylcarbamate

[1148]¹H-NMR(CDCl₃):δ 1.54(9H, s), 2.82(6H, s), 3.14(2H, t, J=6.5 Hz),4.25(2H, t, J=6.8 Hz), 6.63(1H, s), 6.91(2H, d, J=8.9 Hz), 7.23-7.30(2H,m), 7.47(1H, td, J=6.8 Hz, 1.6 Hz), 7.58(2H, d, J=8.9 Hz), 8.25(1H, dd,J=7.8 Hz, 1.6 Hz), 8.84(1H, br s), 11.99(1H, s) (+)ESI-MS(m/z):505(M+Na)⁺

EXAMPLE 175

[1149] To a solution of tert-butyl4-[2-(4-{[2-(dimethylamino)benzoyl]amino}phenoxy)ethyl]-1,3-thiazol-2-ylcarbamate(260 mg) in dichloromethane (2.6 ml) was added trifluoroacetic acid(0.623 ml). The mixture was stirred for 11 hours, quenched with 10%aqueous potassium carbonate solution, and extracted withdichloromethane. The organic layer was washed with brine, dried overmagnesium sulfate, filtered and concentrated in vacuo. The residue waspurified by column chromatography on silica gel eluting with hexane:ethyl acetate (2:1 v/v) to giveN-{4-[2-(2-amino-1,3-thiazol-4-yl)ethoxy]phenyl}-2-(dimethylamino)benzamide(81 mg) as pale brown powder.

[1150]¹H-NMR(CDCl₃):δ 2.82(6H, s), 3.02(2H, t, J=6.8 Hz), 4.25(2H, t,J=7.0 Hz), 6.27(1H, s), 6.92(2H, d, J=8.9 Hz), 7.22-7.30(2H, m),7.43-7.50(1H, m), 7.57(2H, d, J=8.9 Hz), 8.25(1H, dd, J=7.6, 1.6 Hz),11.98(1H, s) (+)ESI-MS(m/z): 583(M+H)⁺

[1151] Preparation 112

[1152] To a solution of 2-(1H-pyrazol-1-yl)ethanol (10 g), triethylamine(18.6 ml) and 4-(dimethylamino)pyridine (1.09 g) in 1,2-dichloroethane(100 ml) was added p-toluenesulfonyl chloride (18.7 g) portionwise atambient temperature. The reaction mixture was stirred for 14 hours,quenched with water, and extracted with 1,2-dichloroethane. The organiclayer was washed with brine, dried over magnesium sulfate, filtered andconcentrated in vacuo. The residue was purified by column chromatographyon silica gel eluting with hexane: ethyl acetate (1:1 v/v) to give2-(1H-pyrazol-1-yl)ethyl 4-methylbenzenesulfonate (21.242 g) as a yellowoil.

[1153]¹H-NMR(CDCl₃):δ 2.43(1H, s), 4.32-4.41(4H, m), 6.21(1H, t, J=2.0Hz), 7.28(2H, d, J=8.2 Hz), 7.41(1H, d, J=2.3 Hz), 7.44(1H, d, J=1.3Hz), (+)ESI-MS(m/z): 267(M+H)⁺

[1154] Preparation 113

[1155] A mixture of 2-(1H-pyrazol-1-yl)ethyl 4-methylbenzenesulfonate(21.242 g) and sodium azide (10.4 g) in N,N-dimethylformamide (210 ml)was stirred at ambient temperature for 15 hours. The solvent was removedand the residue was dissolved with ethyl acetate and water, andextracted in ethyl acetate. The organic layer was washed with water andbrine, dried over magnesium sulfate, filtered and concentrated in vacuoto give 1-(2-azidoethyl)-1H-pyrazole (10.927 g) as a yellow oil. Theproduct was used in the next step without purification.

[1156]¹H-NMR(CDCl₃):δ 3.72(2H, t, J=5.6 Hz), 4.27(2H, t, J=5.6 Hz),6.29(1H, t, J=2.0 Hz), 7.45(1H, d, J=2.0 Hz), 7.57(1H, d, J=1.6 Hz)(+)ESI-MS(m/z): 138(M+H)⁺

[1157] Preparation 114

[1158] A solution of 1-(2-azidoethyl)-1H-pyrazole (10.927 g) in ethanol(100 ml) was hydrogenated over 10% palladium on carbon (50% wet, 2.185g) at ambient temperature under atmospheric pressure of hydrogen for anhour. The reaction mixture was filtered with pad of celite, and filtratewas concentrated in vacuo to give 2-(1H-pyrazol-1-yl)ethylamine (8.169g) as a yellow oil. The product was used in the next step withoutpurification.

[1159]¹H-NMR(CDCl₃):δ 3.15(2H, t, J=5.8 Hz), 4.18(2H, t, J=5.8 Hz),6.26(1H, t, J=2.0 Hz), 7.43(1H, d, J=2.3 Hz), 7.53(1H, d, J=1.6 Hz)(+)ESI-MS(m/z): 112(M+H)⁺

[1160] Preparation 115

[1161] A mixture of 2-(1H-pyrazol-1-yl)ethylamine (8.169 g),1-fluoro-4-nitrobenzene (12.4 g) and triethylamine (11.2 g) in2,6-dimethyl-2-imidazolidinone (100 ml) was heated at 60° C. for 18hours. The reaction mixture was cooled to ambient temperature, pouredinto water and extracted with ethyl acetate. The organic layer waswashed with water and brine, dried over magnesium sulfate, filtered andconcentrated in vacuo. The residue was purified by column chromatographyon silica gel eluting with hexane: ethyl acetate (4:6→1:9 v/v) to giveN-(4-nitrophenyl)-N-[2-(1H-pyrazol-1-yl)ethyl]amine (7.508 g) as ayellow solid.

[1162]¹H-NMR(CDCl₃):δ 3.63-3.69(2H, m), 4.37-4.41(2H, m), 5.23(1H, s),6.27(1H, t, J=2.1 Hz), 6.51(2H, d, J=9.2 Hz), 7.38(1H, dd, J=2.3 Hz, 0.7Hz), 7.56(1H, dd, J=2.0 Hz, 0.7 Hz), 8.05(2H, d, J=9.2 Hz)(+)ESI-MS(m/z): 255(M+Na)⁺

[1163] Preparation 116

[1164] To a solution ofN-(4-nitrophenyl)-N-[2-(1H-pyrazol-1-yl)ethyl]amine (5.012 g) and4-(dimethylamino)pyridine (264 mg) in tetrahydrofuran (100 ml) was addeddi-tert-butyl dicarbonate (7.07 g) and heated at 50° C. for 1 hour. Thereaction mixture was cooled to ambient temperature and concentrated invacuo. The residue was dissolved in ethyl acetate and water, andextracted with ethyl acetate. The organic layer was washed with brine,dried over magnesium sulfate, filtered and concentrated in vacuo. Theresidue was purified by column chromatography on silica gel eluting withhexane: ethyl acetate (2:1→1:1 v/v) to give tert-butyl4-nitrophenyl[2-(1H-pyrazol-1-yl)ethyl]carbamate (7.051 g) as a yellowsolid.

[1165]¹H-NMR(CDCl₃):δ 1.46(9H, s), 4.11(2H, t, J=5.7 Hz), 4.41(2H, t,J=5.7 Hz), 6.21(1H, t, J=2.0 Hz), 7.03(2H, d, J=9.2 Hz), 7.32(1H, d,J=2.3 Hz), 7.45(1H, d, J=2.0 Hz), 8.08(2H, d, J=9.2 Hz) (+)ESI-MS(m/z):355(M+Na)⁺

[1166] Preparation 117

[1167] A solution of tert-butyl4-nitrophenyl[2-(1H-pyrazol-1-yl)ethyl]carbamate (400 mg) in methanol (5ml) was hydrogenated over 10% palladium on carbon at ambient temperatureunder atmospheric pressure of hydrogen for an hour. The reaction mixturewas filtered with pad of Celite, and filtrate was concentrated in vacuoto give tert-butyl 4-aminophenyl[2-(1H-pyrazol-1-yl)ethyl]carbamate (363mg) as a yellow oil. The product was used in the next step withoutpurification.

[1168]¹H-NMR(CDCl₃):δ 1.38(9H, br s), 3.62(2H, br s), 3.96(2H, t, J=6.2Hz), 4.32(2H, br s), 6.23(1H, t, J=2.0 Hz), 6.57(2H, d, J=8.2 Hz),6.72(2H, br s), 7.38(1H, br s), 7.48(1H, d, J=1.6 Hz) (+)ESI-MS(m/z):525(M+Na)⁺

EXAMPLE 176

[1169] To a solution of 4-methyl-2-(4-methyl-1-piperidinyl)benzoic acid(314 mg), tert-butyl 4-aminophenyl[2-(1H-pyrazol-1-yl)ethyl]carbamate(371 mg) and 1-hydroxybenzotriazole (244 mg) in N,N-dimethylformamide(10 ml) was added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimidehydrochloride (WSC.HCl) (306 mg), followed by triethylamine (162 mg) atambient temperature and the mixture was stirred at 50° C. for 16 hours.The reaction mixture was poured into a mixture of ethyl acetate andwater. The separated organic layer was washed with brine, dried overmagnesium sulfate and concentrated in vacuo. The residue was purified bycolumn chromatography on silica gel eluting with hexane: ethyl acetate(1:1 v/v) to give tert-butyl4-{[4-methyl-2-(4-methyl-1-piperidinyl)benzoyl]amino}phenyl[2-(1H-pyrazol-1-yl)ethyl]carbamate(303 mg) as a greenish yellow oil.

[1170]¹H-NMR(CDCl₃):δ 1.06(3H, d, J=6.3 Hz), 1.31-1.65(12H, m), 1.86(2H,brd, J=11.5 Hz), 2.39(3H, s), 2.84(2H, t, J=8.6 Hz), 3.17(2H, brd,J=11.5 Hz), 4.04(2H, t, J=6.3 Hz), 4.36(2H, brs), 6.24(1H, t, J=2.0 Hz),6.95(1H, brs), 7.09(2H, brs), 7.39(1H, s), 7.48(1H, s), 7.67(2H, d,J=8.6 Hz), 8.17(1H, d, J=8.3 Hz), 12.60(1H, s) (+)ESI-MS(m/z):540(M+Na)⁺

EXAMPLE 177

[1171] To a solution of tert-butyl4-{[4-methyl-2-(4-methyl-1-piperidinyl)benzoyl]amino}phenyl[2-(1H-pyrazol-1-yl)ethyl]carbamate(297 mg) in dichloromethane (10 ml) was added trifluoroacetic acid (981mg). The reaction mixture was stirred at ambient temperature for 14hours, quenched with 10% aqueous potassium carbonate aqueous solution,and extracted with dichloromethane. The organic layer was washed withbrine, dried over magnesium sulfate, filtered and concentrated in vacuo.The residue was recrystallized from ethyl acetate-diisopropyl ether togive4-methyl-2-(4-methyl-1-piperidinyl)-N-(4-{[2-(1H-pyrazol-1-yl)ethyl]amino)phenyl)benzamide(177 mg) as a faintly brown powder.

[1172]¹H-NMR(CDCl₃):δ 1.03(3H, d, J=6.3 Hz), 1.40-1.60(3H, m), 2.38(3H,s), 2.81(2H, t, J=11.5 Hz), 2.91(2H, t, J=6.6 Hz), 3.17(2H, d, J=11.9Hz), 3.47(2H, t, J=6.6 Hz), 4.45(2H, brs), 6.36(1H, d, J=8.3 Hz),6.53(1H, d, J=7.3 Hz), 6.65(2H, d, J=8.9 Hz), 7.04-7.08(2H, m), 7.36(1H,t, J=7.3 Hz), 7.57(2H, d, J=8.9 Hz), 8.17(1H, d, J=8.6 Hz), 12.24(1H, s)(+)ESI-MS(m/z): 444(M+H)⁺

EXAMPLE 178

[1173] The following compound was obtained in substantially the samemanner as in Example 176.

[1174] tert-Butyl4-{[2-(dimethylamino)benzoyl]amino)phenyl[2-(1H-pyrazol-1-yl)ethyl]carbamate

[1175]¹H-NMR(CDCl₃):δ 1.53(9H, s), 2.39(3H, s), 2.80(6H, s), 2.96(2H, t,J=6.6 Hz), 3.49(2H, t, J=6.6 Hz), 6.64(2H, d, J=8.9 Hz), 6.83(1H, d,J=7.3 Hz), 7.04-7.08(2H, m), 7.21(1H, brs), 7.49(2H, d, J=8.6 Hz),7.58(1H, t, J=8.6 Hz), 7.77(1H, d, J=8.3 Hz), 8.14(1H, d, J=8.6 Hz),11.86(1H, s) (+)ESI-MS(m/z): 512(M+Na)⁺

EXAMPLE 179

[1176] The following compound was obtained in substantially the samemanner as in Example 177.

[1177]2-(Dimethylamino)-N-(4-{[2-(1H-pyrazol-1-yl)ethyl]amino}phenyl)benzamide

[1178]¹H-NMR(CDCl₃):δ 2.39(3H, s), 2.80(6H, s), 2.90(2H, t, J=6.6 Hz),3.47(2H, t, J=6.6 Hz), 4.46(2H, brs), 6.36(1H, d, J=7.9 Hz), 6.53(1H, d,J=7.3 Hz), 6.64(2H, d, J=8.9 Hz), 7.04-7.07(2H, m), 7.36(1H, t, J=7.3Hz), 7.48(2H, d, J=8.9 Hz), 8.14(1H, d, J=8.6 Hz), 11.84(1H, s)(+)ESI-MS(m/z): 390(M+H)⁺

EXAMPLE 180

[1179] The following compound was obtained in substantially the samemanner as in Example 176.

[1180] tert-Butyl4-({[6-methyl-2-(4-methyl-1-piperidinyl)-3-pyridinyl]carbonyl}amino)phenyl[2-(1H-pyrazol-1-yl)ethyl]carbamate

[1181]¹H-NMR(CDCl₃):δ 1.04(3H, d, J=6.6 Hz), 1.31-1.52(2H, m), 1.41(9H,s), 1.52-1.70(1H, m), 1.85(2H, brd, J=10.6 Hz), 2.52(3H, s), 3.00(2H, t,J=10.2 Hz), 3.33(2H, brd, J=12.5 Hz), 4.04(2H, t, J=6.3 Hz), 4.37(2H, t,J=6.3 Hz), 6.24(1H, t, J=2.0 Hz), 6.96(1H, brs), 7.02(2H, d, J=7.9 Hz),7.39(1H, d, J=2.0 Hz), 7.48(1H, d, J=2.0 Hz), 7.64(2H, d, J=8.9 Hz),8.35(1H, d, J=7.9 Hz), 11.85(1H, s) (+)ESI-MS(m/z): 541(M+Na)⁺

EXAMPLE 181

[1182] The following compound was obtained in substantially the samemanner as in Example 177.

[1183]6-Methyl-2-(4-methyl-1-piperidinyl)-N-(4-{[2-(1H-pyrazol-1-yl)ethyl]amino}phenyl)nicotinamide

[1184]¹H-NMR(CDCl₃):δ 1.02(3H, d, J=6.3 Hz), 1.30-1.50(2H, m),1.50-1.68(1H, m), 1.83(2H, brd, J=12.9 Hz), 2.51(3H, s), 2.98(2H, dt,J=2.3 Hz, 12.2 Hz), 3.34(2H, brd, J=12.5 Hz), 3.60(2H, brs), 3.99(1H,brs), 4.33-4.37(2H, m), 6.25(1H, t, J=2.0 Hz), 6.62(2H, d, J=8.9 Hz),6.99(1H, d, J=7.9 Hz), 7.36(1H, d, J=2.0 Hz), 7.50-7.62(3H, m), 8.34(1H,d, J=7.9 Hz), 11.50(1H, s) (+)ESI-MS(m/z): 419(M+H)⁺, 441(M+Na)⁺

EXAMPLE 182

[1185] To a solution of tert-butyl4-aminophenyl[2-(1H-pyrazol-1-yl)ethyl]carbamate (363 mg),2-(dimethylamino)-4-methylbenzoic acid (237 mg) and1-hydroxybenzotriazole (221 mg) in N,N-dimethylformamide (7 ml) wasadded 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (276mg) at ambient temperature. The reaction mixture was stirred at 50° C.for 19 hours and concentrated in vacuo. The residue was dissolved inethyl acetate and water, and extracted with ethyl acetate. The organiclayer was washed with water and brine, dried over magnesium sulfate,filtered and concentrated in vacuo. The residue was purified by columnchromatography on silica gel eluting with hexane: ethyl acetate (1:1v/v) to give tert-butyl4-{[2-(dimethylamino)-4-methylbenzoyl]amino}phenyl[2-(1H-pyrazol-1-yl)ethyl]carbamate(348 mg) as a yellow foam.

[1186]¹H-NMR(CDCl₃):δ 1.40(9H, s), 2.39(3H, s), 2.80(6H, s), 4.03(2H, t,J=6.1 Hz), 4.35(2H, t, J=6.1 Hz), 6.24(1H, t, J=2.0 Hz), 7.06-7.09(2H,m), 7.39(1H, d, J=2.0 Hz), 7.49(1H, d, J=1.4 Hz), 7.58(2H, d, J=8.9 Hz),8.14(1H, d, J=8.6 Hz), 12.26(1H, s) (+)ESI-MS(m/z): 486(M+Na)⁺

EXAMPLE 183

[1187] To a solution of tert-butyl4-{[2-(dimethylamino)-4-methylbenzoyl]amino}phenyl[2-(1H-pyrazol-1-yl)ethyl]carbamate(345 mg) in dichloromethane (10 ml) was added trifluoroacetic acid (0.86ml). The reaction mixture was stirred at ambient temperature for 19hours, quenched with 10% aqueous potassium carbonate solution, andextracted with dichloromethane. The organic layer was washed with brine,dried over magnesium sulfate, filtered and concentrated in vacuo. Theresidue was recrystallized from ethyl acetate-diisopropyl ether to give2-(dimethylamino)-4-methyl-N-(4-{[2-(1H-pyrazol-1-yl)ethyl]amino}phenyl)benzamide(215 mg) as a white solid.

[1188]¹H-NMR(DMSO-d₆):δ 2.33(3H, s), 2.74(6H, s), 3.42(2H, br s),4.26(2H, t, J=6.2 Hz), 5.57(1H, br s), 6.22(1H, t, J=2.0 Hz), 6.57(2H,d, J=8.9 Hz), 6.93(1H, d, J=7.9 Hz), 7.07(1H, s), 7.43(2H, d, J=8.9 Hz),7.46(1H, d, J=1.6 Hz), 7.66(1H, d, J=7.6 Hz), 7.72(1H, d, J=2.0 Hz),11.17(1H, s) (+)ESI-MS(m/z): 364(M+H)⁺

[1189] Preparation 118

[1190] The mixture of 2-(1H-pyrazol-1-yl)ethanamine (2.13 g),2-chloro-5-nitropyridine (3.65 g) and triethylamine (4.01 ml) indimethylformamide (11 ml) was heated at 50° C. for 12 hours. Thereaction mixture was concentrated in vacuo. To the residue was addedwater and the mixture was extracted with ethyl acetate. The organiclayer was washed with brine, dried over magnesium sulfate, filtered andconcentrated in vacuo. The residue was recrystallized from ethylacetate-hexane to give5-nitro-N-[2-(1H-pyrazol-1-yl)ethyl]-2-pyridinamine (4.39 g) as paleyellow powder.

[1191]¹H-NMR(DMSO-d₆):δ 3.95(2H, q, J=5.4 Hz), 4.39(2H, t, J=5.7 Hz),5.94(1H, br s), 6.27(1H, t, J=2.4 Hz), 6.36(1H, d, J=9.2 Hz), 7.34(1H,d, J=2.2 Hz), 7.56(1H, d, J=1.4 Hz), 8.14(1H, dd, J=9.2 Hz, 2.7 Hz),9.02(1H, d, J=2.7 Hz) (+)ESI-MS(m/z): 234(M+H)⁺

[1192] Preparation 119

[1193] To a solution of5-nitro-N-[2-(1H-pyrazol-1-yl)ethyl]-2-pyridinamine (4.39 g) intetrahydrofuran (35 ml) was added di-t-butyl dicarbonate (6.16 g). Themixture was stirred at ambient temperature for 15 hours. The reactionmixture was concentrated in vacuo. The residue was dissolved in ethylacetate and water, and extracted with ethyl acetate. The organic layerwas washed with water and brine, dried over magnesium sulfate, filteredand concentrated in vacuo. The residue was recrystallized from ethylacetate-hexane to give tert-butyl5-nitro-2-pyridinyl[2-(1H-pyrazol-1-yl)ethyl]carbamate (6.23 g) as apale yellow powder.

[1194]¹H-NMR(CDCl₃):δ 1.50(9H, s), 4.42-4.55(4H, m), 6.19(1H, t, J=1.9Hz), 7.30(1H, d, J=2.4 Hz), 7.44(1H, d, J=1.4 Hz), 8.05(1H, d, J=9.5Hz), 8.35(1H, dd, J=5.9 Hz, 2.7 Hz), 9.16(1H, d, J=3.2 Hz)(+)ESI-MS(m/z): 356(M+Na)⁺

[1195] Preparation 120

[1196] A solution of tert-butyl5-nitro-2-pyridinyl[2-(1H-pyrazol-1-yl)ethyl]carbamate (1.0 g) inmethanol (10 ml) was hydrogenated over 10% palladium on carbon (0.2 g,50% wet) at ambient temperature under atmospheric pressure of hydrogenfor an hour. The reaction mixture was filtered through a short pad ofcelite, and the filtrate was concentrated in vacuo to give tert-butyl5-amino-2-pyridinyl[2-(1H-pyrazol-1-yl)ethyl]carbamate (0.9 g) as a paleyellow oil.

[1197]¹H-NMR(CDCl₃):δ 1.42(9H, s), 3.65(2H, br s), 4.21(2H, t, J=5.7Hz), 4.38(2H, t, J=5.7 Hz), 6.19(1H, t, J=1.9 Hz), 6.93(1H, dd, J=8.6Hz, 3.0 Hz), 7.07(1H, br d, J=6.8 Hz), 7.37(1H, dd, J=2.4 Hz, 0.8 Hz),7.44(1H, dd, J=2.2 Hz, 0.8 Hz), 7.84(1H, dd, J=3.0 Hz, 0.5 Hz)(+)ESI-MS(m/z): 326(M+Na)⁺

EXAMPLE 184

[1198] To a solution of tert-butyl5-amino-2-pyridinyl[2-(1H-pyrazol-1-yl)ethyl]carbamate (343 mg),4-methyl-2-(4-methyl-1-piperidinyl)benzoic acid (317 mg) and1-hydroxybenzotriazole (208 mg) in N,N-dimethylformamide (3 ml) wasadded 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride(WSC.HCl) (260 mg), followed by triethylamine (0.24 ml) at ambienttemperature. The reaction mixture was stirred at ambient temperature for13 hours and concentrated in vacuo. The residue was dissolved in ethylacetate and water, and extracted with ethyl acetate. The organic layerwas washed with water and brine, dried over magnesium sulfate, filteredand concentrated in vacuo. The residue was purified by columnchromatography on silica gel eluting with hexane: ethyl acetate(6:1→4:1→1:1 v/v) to give tert-butyl5-{[4-methyl-2-(4-methyl-1-piperidinyl)benzoyl]amino}-2-pyridinyl[2-(1H-pyrazol-1-yl)ethyl]carbamate(0.274 g) as a pale yellow foam.

[1199]¹H-NMR(CDCl₃):δ 1.08(3H, d, J=6.5 Hz), 1.39-1.53(11H, m),1.48-1.69(1H, m), 1.89(2H, br d, J=12.7 Hz), 2.40(3H, s), 2.86(2H, td,J=11.6 Hz, 2.4 Hz), 3.18(2H, br d, J=11.9 Hz), 4.34(2H, t, J=5.4 Hz),4.44(2H, t, J=5.1 Hz), 6.20(1H, t, J=2.2 Hz), 7.09-7.13(1H, br d, J=8.4Hz), 7.13(1H, s), 7.37(1H, dd, J=2.2 Hz, 0.5 Hz), 7.42-7.46(2H, m),8.19(1H, d, J=7.8 Hz), 8.30(1H, dd, J=8.9 Hz, 3.0 Hz), 8.56(1H, d, J=2.7Hz), 12.90(1H, s) (+)ESI-MS(m/z): 519(M+H)⁺

EXAMPLE 185

[1200] To a solution of tert-butyl5-{[4-methyl-2-(4-methyl-1-piperidinyl)benzoyl]amino)-2-pyridinyl[2-(1H-pyrazol-1-yl)ethyl]carbamate(235.7 mg) in dichloromethane (2.4 ml) was added trifluoroacetic acid(0.525 ml). The mixture was stirred for 60 hours, quenched with 10%aqueous potassium carbonate solution, and extracted withdichloromethane. The organic layer was washed with brine, dried overmagnesium sulfate, filtered and concentrated in vacuo. The residue waspurified by column chromatography on silica gel eluting with hexane:ethyl acetate (6:1→4:1→1:1 v/v) to give4-methyl-2-(4-methyl-1-piperidinyl)-N-(6-{[2-(1H-pyrazol-1-yl)ethyl]amino}-3-pyridinyl)benzamide(120 mg) as a pale brown powder.

[1201]¹H-NMR(CDCl₃):δ 1.05(3H, d, J=6.2 Hz), 1.44(2H, qd, J=12.7 Hz, 3.5Hz), 1.54-1.63(1H, m), 1.86(2H, br d, J=13.5 Hz), 2.39(3H, s), 2.83(2H,td, J=11.9 Hz, 2.2 Hz), 3.17(2H, d, J=12.2 Hz), 3.81(2H, q, J=5.9 Hz),4.38(2H, t, J=5.1 Hz), 4.67(1H, t, J=5.9 Hz), 6.24(1H, t, J=1.9 Hz),6.41(1H, d, J=8.9 Hz), 7.08(1H, d, J=6.8 Hz), 7.09(1H, s), 7.36(1H, d,J=2.4 Hz), 7.55(1H, d, J=1.1 Hz), 8.11-8.24(3H, m), 12.45(1H, s)(+)ESI-MS(m/z): 419(M+H)⁺

EXAMPLE 186

[1202] To a solution of 2-(2-pyridinylacetyl)-5-isoindolinamine (895mg), 6-methyl-2-(4-methyl-1-piperidinyl)nicotinic acid (828 mg) andbenzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate(PyBOP) (2.21 g) in N,N-dimethylformamide (30 ml) was addeddiisopropylethylamine (913 mg) at ambient temperature and the mixturewas stirred at the same temperature for 20 hours. The mixture was pouredinto a mixture of ethyl acetate, water and 6N hydrochloric acid, and theseparated organic layer was washed with water and brine, dried overmagnesium sulfate and evaporated in vacuo. The residue was purified bycolumn chromatography on silica gel eluting with ethyl acetate to give6-methyl-2-(4-methyl-1-piperidinyl)-N-[2-(2-pyridinylacetyl)-2,3-dihydro-1H-isoindol-5-yl]nicotinamide(815 mg) as white crystals.

[1203]¹H-NMR(DMSO-d₆):δ 0.89(3H, d, J=6.1 Hz), 1.1-1.4(3H, m),1.6-1.8(2H, m), 2.39(3H, s), 2.75-2.95(2H, m), 3.4-3.8(6H, m),6.8-7.5(6H, m), 7.65-7.8(2H, m), 8.51(1H, d, J=4.1 Hz), 10.46(1H, s)(+)ESI-MS(m/z): 492(M+Na)⁺

EXAMPLE 187

[1204] The following compound was obtained in substantially the samemanner as in Example 186.

[1205]4-Methyl-2-(4-methyl-1-piperidinyl)-N-[2-(2-pyridinylacetyl)-2,3-dihydro-1H-isoindol-5-yl]benzamide

[1206]¹H-NMR(DMSO-d₆):δ 0.96(3H, d, J=6.0 Hz), 1.2-1.45(3H, m),1.7-1.9(2H, m), 2.34(3H, s), 2.7-2.9(2H, m), 3.05-3.2(2H, m),3.4-3.8(6H, m), 7.0-7.5(6H, m), 7.65-7.85(3H, m), 8.5-8.55(1H, m),11.90(1H, s) (+)ESI-MS(m/z): 469(M+H)⁺, 491(M+Na)⁺

[1207] Preparation 121

[1208] To a solution of 2-(phenylacetyl)-5-isoindolinamine (1.008 g),2-chloro-6-methylnicotinic acid (754 mg) andbenzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate(PyBOP) (2.70 g) in N,N-dimethylformamide (30 ml) was addeddiisopropylethylamine (1.03 g) at ambient temperature and the mixturewas stirred at the same temperature for 20 hours. The mixture was pouredinto a mixture of ethyl acetate, water and 6N hydrochloric acid, and theseparated organic layer was washed with water and brine, dried overmagnesium sulfate and evaporated in vacuo. The residue was purified bycolumn chromatography on silica gel eluting with hexane: ethyl acetate(1:1 v/v) to give2-chloro-6-methyl-N-[2-(phenylacetyl)-2,3-dihydro-1H-isoindol-5-yl]nicotinamide(1.19 g) as a pale brown powder.

[1209]¹H-NMR(DMSO-d₆):δ 2.53(3H, s), 3.71(2H, s), 4.6-5.0(4H, m),6.45-6.55(2H, m), 6.9-7.0(1H, m), 7.2-7.5(7H, m), 10.62(1H, s)(+)ESI-MS(m/z): 406(M+H)⁺

EXAMPLE 188

[1210] To a solution of2-chloro-6-methyl-N-[2-(phenylacetyl)-2,3-dihydro-1H-isoindol-5-yl]nicotinamide(1.18 g) in acetonitrile (15 ml) was added 4-methylpiperidine (865 mg)and the mixture was refluxed for 16 hours. The mixture was evaporated invacuo and the residue was purified by column chromatography on silicagel eluting with hexane: ethyl acetate (2:1 v/v) to give6-methyl-2-(4-methyl-1-piperidinyl)-N-[2-(phenylacetyl)-2,3-dihydro-1H-isoindol-5-yl]nicotinamide(440 mg) as white crystals.

[1211]¹H-NMR(DMSO-d₆):δ 0.88(3H, d, J=6.2 Hz), 1.1-1.7(5H, m), 2.39(3H,s), 2.7-2.9(2H, m), 3.55-3.7(2H, m), 4.64(2H, d, J=8.5 Hz), 4.89(2H, d,J=8.5 Hz), 6.82(1H, d, J=7.6 Hz), 7.2-7.4(6H, m), 7.5-7.6(1H, m),7.7-7.9(3H, m), 10.56(1H, s) (−)ESI-MS(m/z): 467(M−H)⁻

[1212] Preparation 122

[1213] To a solution ofN-(4-aminophenyl)-2-[6-(2,5-dimethyl-1H-pyrrol-1-yl)-2-pyridinyl]acetamide(3.50 g), 2-chloro-6-methylnicotinic acid (1.87 g) andbenzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate(PyBOP) (6.82 g) in N,N-dimethylformamide (50 ml) was addeddiisopropylethylamine (4.24 g) at ambient temperature and the mixturewas stirred at the same temperature for 24 hours. The mixture was pouredinto a mixture of ethyl acetate, water and 6N hydrochloric acid, and theseparated organic layer was washed with water and brine, dried overmagnesium sulfate and evaporated in vacuo. The residue was purified bycolumn chromatography on silica gel eluting with ethyl acetate to give2-chloro-N-[4-({[6-(2,5-dimethyl-1H-pyrrol-1-yl)-2-pyridinyl]acetyl}amino)phenyl]-6-methylnicotinamide(4.15 g) as a brown powder.

[1214]¹H-NMR(DMSO-d₆):δ 1.99(3H, s), 2.04(6H, s), 3.87(2H, s), 5.78(2H,s), 7.29(1H, d, J=7.6 Hz), 7.38(1H, dd, J=7.6 Hz, 6.5 Hz), 7.5-7.7(4H,m), 7.9-8.0(2H, m), 10.25(1H, s), 10.49(1H, s) (+)ESI-MS(m/z):474(M+H)⁺, 496(M+Na)⁺

EXAMPLE 189

[1215] To a solution of2-chloro-N-[4-({[6-(2,5-dimethyl-1H-pyrrol-1-yl)-2-pyridinyl]acetyl}amino)phenyl]-6-methylnicotinamide(1.12 g) in acetonitrile (30 ml) was added 4-methylpiperidine (703 mg)and the mixture was refluxed for 20 hours. The mixture was evaporated invacuo and the residue was purified by column chromatography on silicagel eluting with ethyl acetate to giveN-[4-({[6-(2,5-dimethyl-1H-pyrrol-1-yl)-2-pyridinyl]acetyl}amino)phenyl]-6-methyl-2-(4-methyl-1-piperidinyl)nicotinamide(975 mg) as a brown powder.

[1216]¹H-NMR(DMSO-d₆):δ 0.88(3H, d, J=6.2 Hz), 1.15-1.75(5H, m),2.04(6H, s), 2.7-2.95(2H, m), 3.55-3.7(2H, m), 3.87(2H, s), 5.77(2H, s),6.82(1H, d, J=7.7 Hz), 7.29(1H, d, J=7.8 Hz), 7.44(1H, d, J=7.5 Hz),7.55(1H, d, J=9.0 Hz), 7.64(1H, d, J=9.0 Hz), 7.73(1H, d, J=7.5 Hz),7.95(1H, dd, J=7.8 Hz, 7.7 Hz), 10.22(1H, s), 10.48(1H, s)(+)ESI-MS(m/z): 537(M+H)⁺, 559(M+Na)⁺

EXAMPLE 190

[1217] To a suspension ofN-[4-({[6-(2,5-dimethyl-1H-pyrrol-1-yl)-2-pyridinyl]acetyl}amino)phenyl]-6-methyl-2-(4-methyl-1-piperidinyl)nicotinamide(950 mg) in a mixture of ethanol (40 ml) and water (10 ml) were addedhydroxylamine hydrochloride (1.23 g) and triethylamine (358 mg) atambient temperature. The mixture was refluxed for 6 hours and evaporatedto dryness. The residue was extracted from ethyl acetate and the organiclayer was washed with brine, dried over magnesium sulfate and evaporatedin vacuo. The residue was purified by column chromatography on silicagel eluting with ethyl acetate to giveN-(4-{[(6-amino-2-pyridinyl)acetyl]amino}phenyl)-6-methyl-2-(4-methyl-1-piperidinyl)nicotinamide(458 mg) as white crystals.

[1218]¹H-NMR(DMSO-d₆):δ 0.89(3H, d, J=6.2 Hz), 1.1-1.75(4H, m),2.3-2.4(1H, m), 2.39(3H, s), 2.7-2.9(2H, m), 3.55(2H, s), 4.55-4.75(2H,m), 5.91(2H, brs), 6.31(1H, d, J=8.0 Hz), 6.47(1H, d, J=7.1 Hz),6.82(1H, d, J=7.6 Hz), 7.32(1H, dd, J=8.0 Hz, 7.1 Hz), 7.55-7.7(4H, m),7.75(1H, d, J=7.6 Hz), 10.19(1H, s), 10.48(1H, s) (+)ESI-MS(m/z):459(M+H)⁺, 481(M+Na)⁺

[1219] Preparation 123

[1220] To a 20% solution of sodium ethoxide (108 ml) was added dropwise2-hydrazinoethanol (80%v/v aqueous solution) (31.8 ml) at 5° C.,followed by addition of a solution of 2-chloroacetonitrile (27.40 g) inethanol (100 ml). The mixture was refluxed for 18 hours and cooled toambient temperature and the residue was purified by columnchromatography on silica gel eluting with dichloromethane:methanol (5:1v/v) to give 2-(3-amino-1H-pyrazol-1-yl)ethanol (8.94 g) as a dark brownoil.

[1221]¹H-NMR(DMSO-d₆):δ 3.62(2H, td, J=6.0 Hz, 5.4 Hz), 3.84(2H, t,J=6.0 Hz), 4.46(2H, brs), 4.77(1H, t, J=5.4 Hz), 5.34(1H, d, J=2.2 Hz),7.26(1H, d, J=2.2 Hz) (+)APCI-MS(m/z): 128(M+H)⁺

[1222] Preparation 124

[1223] To a solution of 2-(3-amino-1H-pyrazol-1-yl)ethanol (8.90 g) intoluene (200 ml) were added 2,5-hexanedione (9.59 g) andp-toluenesulfonic acid hydrate (1.33 g) at ambient temperature and themixture was refluxed for 20 hours. The mixture was concentrated to ca.50 ml and purified by column chromatography on silica gel eluting withethyl acetate to give2-[3-(2,5-dimethyl-1H-pyrrol-1-yl)-1H-pyrazol-1-yl]ethanol (7.77 g) as ayellow oil.

[1224]¹H-NMR(DMSO-d₆):δ 2.02(6H, s), 3.74(2H, td, J=6.1 Hz, 5.2 Hz),4.14(2H, t, J=6.1 Hz), 4.92(1H, t, J=5.2 Hz), 5.74(2H, s), 6.24(1H, d,J=2.2 Hz), 7.79(1H, d, J=2.2 Hz) (+)ESI-MS(m/z): 206(M+H)⁺, 228(M+Na)⁺

[1225] Preparation 125

[1226] To a solution of potassium tert-butoxide (2.25 g) intetrahydrofuran (60 ml) was added dropwise a solution of2-[3-(2,5-dimethyl-1H-pyrrol-1-yl)-1H-pyrazol-1-yl]ethanol (4.11 g) intetrahydrofuran (40 ml) at ambient temperature, followed by addition of4-fluronitrobenzene (2.83 g). The mixture was refluxed for 6 hours undernitrogen and poured into a mixture of ethyl acetate and ice-water. Theseparated organic layer was washed with brine, dried over magnesiumsulfate and evaporated in vacuo. The residue was purified by columnchromatography on silica gel eluting with hexane: ethyl acetate (2:1v/v) to give3-(2,5-dimethyl-1H-pyrrol-1-yl)-1-[2-(4-nitrophenoxy)ethyl]-1H-pyrazole(3.34 g) as a pale brown powder.

[1227]¹H-NMR(DMSO-d₆):δ 1.96(6H, s), 4.55(4H, s), 5.73(2H, s), 6.29(1H,d, J=2.4 Hz), 7.1-7.2(2H, m), 7.92(1H, d, J=2.4 Hz), 8.15-8.25(2H, m)(+)ESI-MS(m/z): 327(M+H)⁺

[1228] Preparation 126

[1229] To a solution of3-(2,5-dimethyl-1H-pyrrol-1-yl)-1-[2-(4-nitrophenoxy)ethyl]-1H-pyrazole(3.31 g) in tetrahydrofuran (40 ml) and methanol (40 ml) was added 5%palladium on carbon (1 g, 50% wet) and the mixture was hydrogenated for4 hours at ambient temperature. The catalyst was removed by filtrationand the filtrate was evaporated in vacuo. The residue was purified bycolumn chromatography on silica gel eluting with hexane: ethyl acetate(1:2 v/v) to give4-{2-[3-(2,5-dimethyl-1H-pyrrol-1-yl)-1H-pyrazol-1-yl]ethoxy}aniline(2.46 g) as a pale brown powder.

[1230]¹H-NMR(DMSO-d₆):δ 2.00(6H, s), 4.20(2H, t, J=5.6 Hz), 4.41(2H, t,J=5.6 Hz), 4.63(2H, brs), 5.74(2H, s), 6.28(1H, d, J=2.4 Hz),6.4-6.5(2H, m), 6.55-6.65(2H, m), 7.87(1H, d, J=2.4 Hz) (+)ESI-MS(m/z):297(M+H)⁺

EXAMPLE 191

[1231] To a solution of4-{2-[3-(2,5-dimethyl-1H-pyrrol-1-yl)-1H-pyrazol-1-yl]ethoxy}aniline(1.30 g), 6-methyl-2-(4-methyl-1-piperidinyl)nicotinic acid (1.03 g) andbenzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate(PyBOP) (2.74 g) in N,N-dimethylformamide (50 ml) was addeddiisopropylethylamine (1.73 g) at ambient temperature and the mixturewas stirred at the same temperature for 24 hours. The mixture was pouredinto a mixture of ethyl acetate, water and 6N hydrochloric acid, and theseparated organic layer was washed with water and brine, dried overmagnesium sulfate and evaporated in vacuo. The residue was purified bycolumn chromatography on silica gel eluting with ethyl acetate to giveN-(4-{2-[3-(2,5-dimethyl-1H-pyrrol-1-yl)-1H-pyrazol-1-yl]ethoxy}phenyl)-6-methyl-2-(4-methyl-1-piperidinyl)nicotinamide(1.40 g) as a brown powder.

[1232]¹H-NMR(DMSO-d₆):δ 0.88(3H, t, J=6.1 Hz), 1.1-1.3(2H, m),1.4-1.75(3H, m), 1.99(6H, s), 2.39(3H, s), 2.7-2.9(2H, m), 3.55-3.7(2H,m), 4.35(2H, t, J=4.9 Hz), 4.49(2H, t, J=4.9 Hz), 5.73(2H, s), 6.28(1H,d, J=2.4 Hz), 6.81(1H, d, J=7.6 Hz), 6.88(2H, d, J=9.0 Hz), 7.60(2H, d,J=9.0 Hz), 7.73(1H, d, J=7.6 Hz), 7.90(1H, d, J=2.4 Hz), 10.41(1H, s)(+)ESI-MS(m/z): 513(M+H)⁺, 535(M+Na)⁺

EXAMPLE 192

[1233] To a suspension ofN-(4-{2-[3-(2,5-dimethyl-1H-pyrrol-1-yl)-1H-pyrazol-1-yl]ethoxy}phenyl)-6-methyl-2-(4-methyl-1-piperidinyl)nicotinamide(1.39 g) in a mixture of ethanol (40 ml) and water (10 ml) were addedhydroxylamine hydrochloride (1.89 g) and triethylamine (549 mg) atambient temperature. The mixture was refluxed for 6 hours and evaporatedto dryness. The residue was extracted from ethyl acetate and the organiclayer was washed with brine, dried over magnesium sulfate and evaporatedin vacuo. The residue was purified by column chromatography on silicagel eluting with ethyl acetate methanol (10:1 v/v) to giveN-{4-[2-(3-amino-1H-pyrazol-1-yl)ethoxy]phenyl)-6-methyl-2-(4-methyl-1-piperidinyl)nicotinamide(462 mg) as white crystals.

[1234]¹H-NMR(DMSO-d₆):δ 0.88(3H, d, J=6.0 Hz), 1.0-1.3(2H, m),1.35-1.7(3H, m), 2.38(3H, s), 2.65-2.9(2H, m), 3.55-3.75(2H, m),4.19(2H, s), 4.56(2H, brs), 5.38(1H, d, J=2.0 Hz), 6.81(2H, d, J=8.8Hz), 6.89(2H, d, J=8.8 Hz), 7.36(1H, d, J=2.0 Hz), 7.61(2H, d, J=8.8Hz), 7.73(1H, d, J=7.6 Hz), 10.39(1H, s) (+)ESI-MS(m/z): 435(M+H)⁺,457(M+Na)⁺

[1235] Preparation 127

[1236] To a solution of 4-nitroaniline (27.62 g) and triethylamine (24.3g) in acetonitrile (280 ml) was added dropwise chloroacetyl chloride(24.8 g) at 5° C. and the mixture was stirred at ambient temperature for20 hours. The precipitates were collected by filtration and washed withwater and diisopropyl ether, and dried in vacuo over phosphoruspentoxide to give 2-chloro-N-(4-nitrophenyl)acetamide (33.99 g) as ayellow powder.

[1237]¹H-NMR(DMSO-d₆):δ 4.35(2H, s), 7.75-7.9(2H, m), 8.2-8.3(2H, m),10.91(1H, s) (−)APCI-MS(m/z): 213(M−H)⁻

[1238] Preparation 128

[1239] To a suspension of sodium hydride (60% oil dispersion) (1.32 g)in N,N-dimethylformamide (40 ml) was added a solution of pyrazole (2.25g) in N,N-dimethylformamide (20 ml) at 5° C. and the mixture was stirredat ambient temperature for an hour. To this mixture was added dropwise asolution of 2-chloro-N-(4-nitrophenyl)acetamide (6.44 g) inN,N-dimethylformamide (40 ml) and stirred at 50° C. for 8 hours. Themixture was poured into a mixture of ethyl acetate and ice-water and theseparated organic layer was washed with water and brine, dried overmagnesium sulfate and evaporated in vacuo. The residue was purified bycolumn chromatography on silica gel eluting with hexane: ethyl acetate(1:2 v/v) to give N-(4-nitrophenyl)-2-(1H-pyrazol-1-yl)acetamide (3.49g) as a yellow powder.

[1240]¹H-NMR(DMSO-d₆):δ 5.11(2H, s), 6.30(1H, dd, J=2.3 Hz, 1.6 Hz),7.48(1H, d, J=1.6 Hz), 7.79(1H, d, J=2.3 Hz), 7.85-7.95(2H, m),8.2-8.3(2H, m), 10.94(1H, s) (+)ESI-MS(m/z): 247(M+H)⁺

[1241] Preparation 129

[1242] To a solution of N-(4-nitrophenyl)-2-(1H-pyrazol-1-yl)acetamide(3.47 g) in tetrahydrofuran (40 ml) and methanol (40 ml) was added 5%palladium on carbon (1 g, 50% wet) and the mixture was hydrogenated for4 hours at ambient temperature. The catalyst was removed by filtrationand the filtrate was evaporated in vacuo. The residue was purified bycolumn chromatography on silica gel eluting with ethyl acetate:methanol(10:1 v/v) to give N-(4-aminophenyl)-2-(1H-pyrazol-1-yl)acetamide (2.30g) as a pale brown powder.

[1243]¹H-NMR(DMSO-d₆):δ 4.90(2H, brs), 4.92(2H, s), 6.26(1H, dd, J=2.2Hz, 1.7 Hz), 6.51(2H, d, J=8.7 Hz), 7.21(2H, d, J=8.7 Hz), 7.45(1H, d,J=1.7 Hz), 7.73(1H, d, J=2.2 Hz), 9.87(1H, s) (+)ESI-MS(m/z): 217(M+H)⁺,239(M+Na)⁺

EXAMPLE 193

[1244] To a solution of N-(4-aminophenyl)-2-(1H-pyrazol-1-yl)acetamide(648 mg), 6- methyl-2-(4-methyl-1-piperidinyl)nicotinic acid (702 mg)and benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate(PyBOP) (1.87 g) in N,N-dimethylformamide (50 ml) was addeddiisopropylethylamine (775 mg) at ambient temperature and the mixturewas stirred at the same temperature for 24 hours. The mixture was pouredinto a mixture of ethyl acetate, water and 6N hydrochloric acid, and theseparated organic layer was washed with water and brine, dried overmagnesium sulfate and evaporated in vacuo. The residue was purified bycolumn chromatography on silica gel eluting with ethyl acetate to give6-methyl-2-(4-methyl-1-piperidinyl)-N-{4-[(1H-pyrazol-1-ylacetyl)amino]phenyl}nicotinamide(1.01 g) as white crystals.

[1245]¹H-NMR(DMSO-d₆):δ 0.88(3H, d, J=6.2 Hz), 1.1-1.35(2H, m),1.4-1.8(3H, m), 2.39(3H,-s), 2.7-2.9(2H, m), 3.6-3.75(2H, m), 5.00(2H,s), 6.28(1H, dd, J=1.7 Hz, 1.5 Hz), 6.82(2H, d, J=7.6 Hz), 7.46(1H, d,J=1.5 Hz), 7.54(2H, d, J=9.0 Hz), 7.67(2H, d, J=9.0 Hz), 7.70(1H, d,J=7.6 Hz), 7.77(1H, d, J=1.7 Hz), 10.29(1H, s), 10.50(1H, s)(+)ESI-MS(m/z): 433(M+H)⁺, 455(M+Na)⁺

EXAMPLE 194

[1246] The following compound was obtained in substantially the samemanner as in Example 193.

[1247]2-(Dimethylamino)-4-methyl-N-{4-[(1H-pyrazol-1-ylacetyl)amino]phenyl}benzamide

[1248]¹H-NMR(DMSO-d₆):δ 2.34(3H, s), 2.76(6H, s), 5.00(2H, s), 6.28(1H,dd, J=2.1 Hz, 1.5 Hz), 6.95(1H, d, J=8.0 Hz), 7.10(1H, s), 7.46(1H, d,J=1.5 Hz), 7.55(2H, d, J=9.0 Hz), 7.67(2H, d, J=9.0 Hz), 7.68(1H, d,J=8.0 Hz), 7.77(1H, d, J=2.1 Hz), 10.29(1H, s), 11.53(1H, s)(+)ESI-MS(m/z): 378(M+H)⁺, 400(M+Na)⁺

[1249] Preparation 130

[1250] To a solution of 5-nitroindoline (11.72 g), 1H-pyrazol-1-ylaceticacid (9.0 g) and benzotriazol-1-yl-oxytripyrrolidinophosphoniumhexafluorophosphate (PyBOP) (44.6 g) in N,N-dimethylformamide (40 ml)was added dropwise diisopropylethylamine (18.5 g) at ambient temperatureand the mixture was stirred at 30° C. for 20 hours. The mixture waspoured into a mixture of ethyl acetate and water and the separatedorganic layer was washed with water and brine, dried over magnesiumsulfate and evaporated in vacuo. The residue was purified by columnchromatography on silica gel eluting with ethyl acetate to give5-nitro-1-(1H-pyrazol-1-ylacetyl)indoline (12.99 g) as a yellow powder.

[1251]¹H-NMR(DMSO-d₆):δ 3.31(2H, t, J=8.7 Hz), 4.32(2H, t, J=8.7 Hz),5.33(2H, s), 6.31(1H, dd, J=2.4 Hz, 1.9 Hz), 7.49(1H, d, J=1.9 Hz),7.72(1H, d, J=2.4 Hz), 8.1-8.2(3H, m) (−)ESI-MS(m/z): 271(M−H)⁻

[1252] Preparation 131

[1253] To a solution of 5-nitro-1-(1H-pyrazol-1-ylacetyl)indoline (12.2g) in N,N-dimethylformamide (100 ml) was added 5% palladium on carbon (3g, 50% wet) and the mixture was hydrogenated for 4 hours at 45° C. Thecatalyst was removed by filtration and washed with N,N-dimethylformamide(20 ml). The filtrate containing1-(1H-pyrazol-1-ylacetyl)-5-indolinamine was used in the next stepwithout further purification.

EXAMPLE 195

[1254] To a solution of 1-(1H-pyrazol-1-ylacetyl)-5-indolinamine (905mg), 4-methyl-2-(4-methyl-1-piperidinyl)benzoic acid (871 mg) andbenzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate(PyBOP) (2.33 g) in N,N-dimethylformamide (30 ml) was added dropwisediisopropylethylamine (966 mg) at ambient temperature and the mixturewas stirred at the same temperature for 20 hours. The mixture was pouredinto a mixture of ethyl acetate and water and the separated organiclayer was washed with water and brine, dried over magnesium sulfate andevaporated in vacuo. The residue was purified by column chromatographyon silica gel eluting with ethyl acetate to give4-methyl-2-(4-methyl-1-piperidinyl)-N-[1-(1H-pyrazol-1-ylacetyl)-2,3-dihydro-1H-indol-5-yl]benzamide(865 mg) as a pale brown powder.

[1255]¹H-NMR(DMSO-d₆):δ 0.95(3H, d, J=6.0 Hz), 1.3-1.6(3H, m),1.7-1.85(2H, m), 2.34(3H, s), 2.7-2.9(2H, m), 3.05-3.2(2H, m), 3.23(2H,t, J=8.3 Hz), 4.20(2H, t, J=8.3 Hz), 5.24(2H, s), 6.30(1H, dd, J=2.2 Hz,1.7 Hz), 7.04(2H, d, J=8.0 Hz), 7.16(1H, d, J=1.5 Hz), 7.39(1H, dd,J=8.0 Hz, 1.5 Hz), 7.47(1H, d, J=1.7 Hz), 7.72(1H, d, J=2.1 Hz),7.79(1H, d, J=8.0 Hz), 7.82(1H, s), 7.96(1H, d, J=8.0 Hz), 11.85(1H, s)(+)ESI-MS(m/z): 458(M+H)⁺, 480(M+Na)⁺

EXAMPLE 196

[1256] The following compound was obtained in substantially the samemanner as in Example 195.

[1257]6-Methyl-2-(4-methyl-1-piperidinyl)-N-[1-(1H-pyrazol-1-ylacetyl)-2,3-dihydro-1H-indol-5-yl]nicotinamide

[1258]¹H-NMR(DMSO-d₆):δ 0.88(3H, d, J=6.2 Hz), 1.0-1.3(2H, m),1.5-1.75(3H, m), 2.39(3H, s), 2.7-2.9(2H, m), 3.15-3.3(2H, m),3.6-3.75(2H, m), 4.20(2H, t, J=8.3 Hz), 5.23(2H, s), 6.30(1H, dd, J=1.6Hz, 1.5 Hz), 6.81(1H, d, J=7.7 Hz), 7.40(1H, dd, J=8.6 Hz, 1.7 Hz),7.47(1H, d, J=1.6 Hz), 7.71(1H, d, J=1.5 Hz), 7.75(1H, d, J=1.7 Hz),7.93(1H, d, J=8.6 Hz), 10.48(1H, s) (+)ESI-MS(m/z): 459(M+H)⁺,481(M+Na)⁺

EXAMPLE 197

[1259] The following compound was obtained in substantially the samemanner as in Example 195.

[1260]2-(Dimethylamino)-4-methyl-N-[1-(1H-pyrazol-1-ylacetyl)-2,3-dihydro-1H-indol-5-yl]benzamide

[1261]¹H-NMR(DMSO-d₆):δ 2.34(3H, s), 2.76(6H, s), 3.22(2H, t, J=8.5 Hz),4.20(2H, t, J=8.5 Hz), 5.24(2H, s), 6.30(1H, dd, J=2.0 Hz, 1.8 Hz),6.95(1H, d, J=7.9 Hz), 7.10(1H, d, J=1.8 Hz), 7.42(1H, dd, J=7.9 Hz, 1.8Hz), 7.47(1H, d, J=1.8 Hz), 7.67(1H, d, J=8.6 Hz), 7.72(1H, d, J=2.0Hz), 7.93(1H, d, J=8.6 Hz), 11.54(1H, s) (+)ESI-MS(m/z): 404(M+H)⁺,426(M+Na)⁺

EXAMPLE 198

[1262] The following compound was obtained in substantially the samemanner as in Example 195.

[1263]4-Chloro-2-(dimethylamino)-N-[1-(1H-pyrazol-1-ylacetyl)-2,3-dihydro-1H-indol-5-yl]benzamide

[1264]¹H-NMR(DMSO-d₆):δ 2.89(6H, s), 3.21(2H, t, J=8.3 Hz), 4.20(2H, t,J=8.3 Hz), 5.24(2H, s), 6.30(1H, dd, J=1.9 Hz, 1.5 Hz), 7.02(1H, dd,J=8.2 Hz, 1.9 Hz), 7.10(1H, d, J=1.9 Hz), 7.42(1H, dd, J=8.2 Hz, 2.0Hz), 7.52(1H, d, J=8.3 Hz), 7.72(1H, d, J=2.0 Hz), 7.72(1H, s), 7.93(1H,d, J=8.3 Hz), 10.73(1H, s)

EXAMPLE 199

[1265] To a solution ofN-(2,3-dihydro-1H-indol-5-yl)-6-methyl-2-(4-methyl-1-piperidinyl)nicotinamide(351 mg), 1H-tetrazol-1-ylacetic acid (128 mg) andbenzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate(PyBOP) (325 mg) in N,N-dimethylformamide (30 ml) was added dropwisediisopropylethylamine (259 mg) at ambient temperature and the mixturewas stirred at the same temperature for 20 hours. The mixture was pouredinto a mixture of ethyl acetate and water and the separated organiclayer was washed with water and brine, dried over magnesium sulfate andevaporated in vacuo. The residue was purified by column chromatographyon silica gel eluting with ethyl acetate to give6-methyl-2-(4-methyl-1-piperidinyl)-N-[1-(1H-tetrazol-1-ylacetyl)-2,3-dihydro-1H-indol-5-yl]nicotinamide(333 mg) as a pale brown powder.

[1266]¹H-NMR(DMSO-d₆):δ 0.88(3H, d, J=6.1 Hz), 1.0-1.3(2H, m),1.4-1.7(3H, m), 2.39(3H, s), 2.7-2.9(2H, m), 3.26(2H, t, J=8.2 Hz),3.6-3.8(2H, m), 4.25(2H, t, J=8.2 Hz), 5.73(2H, s), 6.81(1H, d, J=7.6Hz), 7.42(1H, dd, J=8.6 Hz, 1.7 Hz), 7.73(1H, d, J=7.6 Hz), 7.79(1H, d,J=1.7 Hz), 7.90(1H, d, J=8.6 Hz), 9.37(1H, s), 10.50(1H, s)(+)ESI-MS(m/z): 461(M+H)⁺, 483(M+Na)⁺

EXAMPLE 200

[1267] To a solution of 2-(1H-pyrazol-1-ylacetyl)-5-isoindolinamine (895mg), 6-methyl-2-(4-methyl-1-piperidinyl)nicotinic acid (952 mg) andbenzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate(PyBOP) (2.50 g) in N,N-dimethylformamide (40 ml) was added dropwisediisopropylethylamine (955 mg) at ambient temperature and the mixturewas stirred at the same temperature for 20 hours. The mixture was pouredinto a mixture of ethyl acetate and water and the separated organiclayer was washed with water and brine, dried over magnesium sulfate andevaporated in vacuo. The residue was purified by column chromatographyon silica gel eluting with ethyl acetate to give6-methyl-2-(4-methyl-1-piperidinyl)-N-[2-(1H-pyrazol-1-ylacetyl)-2,3-dihydro-1H-isoindol-5-yl]nicotinamide(658 mg) as white powder.

[1268]¹H-NMR(DMSO-d₆):δ 0.96(3H, d, J=5.9 Hz), 1.1-1.4(3H, m),1.6-1.8(2H, m), 2.39(3H, s), 2.75-2.95(2H, m), 3.4-3.8(6H, m), 5.16(2H,s), 6.27(1H, dd, J=1.9 Hz, 1.3 Hz), 7.0-8.0(7H, m), 10.48(1H, s)(+)ESI-MS(m/z): 459(M+H)⁺, 481(M+Na)⁺

EXAMPLE 201

[1269] The following compound was obtained in substantially the samemanner as in Example 200.

[1270]4-Methyl-2-(4-methyl-1-piperidinyl)-N-[2-(1H-pyrazol-1-ylacetyl)-2,3-dihydro-1H-isoindol-5-yl]benzamide

[1271]¹H-NMR(DMSO-d₆):δ 0.96(3H, d, J=5.9 Hz), 1.25-1.5(3H, m),1.7-1.85(2H, m), 2.35(3H, s), 2.7-2.9(2H, m), 3.1-3.25(2H, m), 4.67(2H,d, J=8.9 Hz), 4.92(2H, d, J=8.9 Hz), 5.17(2H, s), 6.28(1H, dd, J=1.9 Hz,1.2 Hz), 7.05(1H, d, J=7.9 Hz), 7.18(1H, s), 7.3-7.45(2H, m), 7.45(1H,d, J=1.2 Hz), 7.54(1H, d, J=9.4 Hz), 7.70(1H, d, J=1.9 Hz), 7.79(1H, d,J=7.9 Hz), 7.92(1H, d, J=4.0 Hz), 11.92 and 11.93(total 1H, s)(+)ESI-MS(m/z): 458(M+H)⁺, 480(M+Na)⁺

EXAMPLE 202

[1272] The following compound was obtained in substantially the samemanner as in Example 200.

[1273]2-(Dimethylamino)-4-methyl-N-[2-(1H-pyrazol-1-ylacetyl)-2,3-dihydro-1H-isoindol-5-yl]benzamide

[1274]¹H-NMR(DMSO-d₆):δ 2.35(3H, s), 2.77(6H, s), 4.66(2H, d, J=8.2 Hz),4.92(2H, d, J=7.9 Hz), 5.18(2H, s), 6.28(1H, dd, J=1.7 Hz, 1.3 Hz),6.96(1H, d, J=7.9 Hz), 7.10(1H, s), 7.3-7.4(2H, m), 7.45(1H, d, J=1.3Hz), 7.55-7.75(3H, m), 7.83(1H, s), 11.58(1H, s) (+)ESI-MS(m/z):404(M+H)⁺, 426(M+Na)⁺

EXAMPLE 203

[1275] The following compound was obtained in substantially the samemanner as in Example 200.

[1276]4-Chloro-2-(dimethylamino)-N-[2-(1H-pyrazol-1-ylacetyl)-2,3-dihydro-1H-isoindol-5-yl]benzamide

[1277]¹H-NMR(DMSO-d₆):δ 2.81(6H, s), 4.66(2H, d, J=8.4 Hz), 4.91(2H, d,J=8.1 Hz), 5.17(2H, s), 6.28(1H, dd, J=2.1 Hz, 1.8 Hz), 7.02(1H, dd,J=8.2 Hz, 1.8 Hz), 7.11(1H, d, J=1.8 Hz), 7.33(1H, d, J=8.2 Hz),7.45(1H, d, J=1.8 Hz), 7.53(1H, d, J=8.2 Hz), 7.70(1H, d, J=1.8 Hz),7.80(1H, s), 10.80(1H, s) (+)ESI-MS(m/z): 446(M+Na)⁺

EXAMPLE 204

[1278] The following compound was obtained in substantially the samemanner as in Example 1.

[1279]2,3-Dimethyl-N-[1-(2-pyridinylacetyl)-2,3-dihydro-1H-indol-5-yl]benzamide

[1280]¹H-NMR(DMSO-d₆):δ 2.24(3H, s), 2.28(3H, s), 3.16(2H, t, J=8.3 Hz),4.01(2H, s), 4.22(2H, t, J=8.3 Hz), 7.12-7.48(6H, m), 7.69-7.83(2H, m),7.97(1H, d, J=8.7 Hz), 8.47-8.54(1H, m), 10.22(1H, s) (+)ESI-MS(m/z):386(M+H)⁺, 408(M+Na)⁺

EXAMPLE 205

[1281] The following compound was obtained in substantially the samemanner as in Example 1.

[1282]2,4-Dimethyl-N-[1-(2-pyridinylacetyl)-2,3-dihydro-1H-indol-5-yl]benzamide

[1283]¹H-NMR(DMSO-d₆):δ 2.31(3H, s), 2.35(3H, s), 3.16(2H, t, J=8.4 Hz),4.00(2H, s), 4.22(2H, t, J=8.4 Hz), 7.04-7.15(2H, m), 7.22-7.50(4H, m),7.67-7.83(2H, m), 7.97(1H, d, J=8.7 Hz), 8.46-8.54(1H, m), 10.13(1H, s)(+)ESI-MS(m/z): 386(M+H)⁺, 408(M+Na)⁺

EXAMPLE 206

[1284] The following compound was obtained in substantially the samemanner as in Preparation 36.

[1285]N-[1-(2-Pyridinylacetyl)-2,3-dihydro-1H-indol-5-yl]-2,4-bis(trifluoromethyl)benzamide

[1286]¹H-NMR(DMSO-d₆): δ 3.18(2H, t, J=8.3 Hz), 4.02(2H, s), 4.23(2H, t,J=8.3 Hz), 7.28(1H, dd, J=5.7 Hz, 7.3 Hz), 7.32-7.43(2H, m), 7.65(1H,s), 7.71-7.82(1H, m), 7.93-8.07(2H, m), 8.17-8.26(2H, m), 8.48-8.54(1H,m), 10.63(1H, s) (+)ESI-MS(m/z): 494(M+H)⁺, 516(M+Na)⁺

EXAMPLE 207

[1287] The following compound was obtained in substantially the samemanner as in Preparation 36.

[1288]N-[1-(2-Pyridinylacetyl)-2,3-dihydro-1H-indol-5-yl]-2,5-bis(trifluoromethyl)benzamide

[1289]¹H-NMR(DMSO-d₆):δ 3.18(2H, t, J=8.3 Hz), 4.02(2H, s), 4.23(2H, t,J=8.3 Hz), 7.28(1H, dd, J=5.5 Hz, 7.1 Hz), 7.32-7.42(2H, m), 7.66(1H,s), 7.71-7.82(1H, m), 8.01(1H, d, J=8.6 Hz), 8.08-8.18(3H, m),8.48-8.53(1H, m), 10.63(1H, s) (+)ESI-MS(m/z): 494(M+H)⁺, 516(M+Na)⁺

[1290] Preparation 132

[1291] A mixture of 2-isopropoxy-4-methylbenzoic acid (2.57 g),tert-butyl 5-amino-1-indolinecarboxylate (3.41 g),1-hydroxybenzotriazole hydrate (2.13 g) and1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide (2.16 g) inN,N-dimethylformamide (30 ml) was stirred at ambient temperatureovernight. The reaction mixture was poured into a mixture of ethylacetate and water, and the organic layer was washed with brine and driedover magnesium sulfate. The solvent was concentrated in vacuo and theprecipitate was collected by filtration to give tert-butyl5-[(2-isopropoxy-4-methylbenzoyl)amino]-1-indolinecarboxylate (4.82 g).

[1292]¹H-NMR(DMSO-d₆): δ 1.38(3H, d, J=6.02 Hz), 1.51(9H, s) 2.36(3H,s),3.07(2H, t, J=8.36 Hz), 3.91(2H, t, J=8.36 Hz), 4.75-4.80(1H, m),6.89(1H, d, J=7.98 Hz), 7.04(1H, s), 7.41(1H, s), 7.63-7.69(2H, m),7.71(1H, d, J=7.98 Hz), 10.01(1H, s)

[1293] Preparation 133

[1294] A mixture of tert-butyl5-[(2-isopropoxy-4-methylbenzoyl)amino]-1-indolinecarboxylate (1.59 g)and trifluoroacetic acid (3.0 ml) in dichloromethane (5 ml) was stirredat ambient temperature for 5 hours. The reaction mixture was evaporatedin vacuo, and the residue was dissolved in a mixture of ethyl acetateand water. The solution was adjusted to pH 8.5 with aqueous potassiumcarbonate solution. The organic layer was washed with brine and driedover magnesium sulfate. The solvent was concentrated in vacuo and theprecipitate was collected by filtration to giveN-(2,3-dihydro-1H-indol-5-yl)-2-isopropoxy-4-methylbenzamide (1.1 g).

[1295]¹H-NMR(DMSO-d₆):δ 1.39(3H, d, J=6.00 Hz), 2.35(3H, s), 2.91(2H, t,J=8.30 Hz), 3.37-3.45(2H, m), 4.75-4.87(1H, s), 5.38(1H, br.s), 6.49(1H,d, J=8.28 Hz), 6.88(1H, d, J=8.02 Hz), 7.02(1H, s), 7.20(1H, dd, J=2.05Hz, 8.28 Hz), 7.43(1H, s), 7.77(1H, d, J=8.02 Hz), 9.84(1H, s)

EXAMPLE 208

[1296] A mixture ofN-(2,3-dihydro-1H-indol-5-yl)-2-isopropoxy-4-methylbenzamide (680 mg),(6-[(tert-butoxycarbonyl)amino]-2-pyridinyl}acetic acid (580 mg),1-hydroxybenzotriazole hydrate (352 mg) and1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide (357 mg) andN,N-dimethylaminopyridine (24 mg) in N,N-dimethylformamide (30 ml) wasstirred at ambient temperature for overnight. The reaction mixture waspoured into a mixture of ethyl acetate and water, and the organic layerwas washed with brine and dried over magnesium sulfate. The solvent wasconcentrated in vacuo, and the precipitate was collected by filtrationto give tert-butyl6-(2-{5-[(2-isopropoxy-4-methylbenzoyl)amino]-2,3-dihydro-1H-indol-1-yl}-2-oxoethyl)-2-pyridinylcarbamate (1.07 g).

[1297]¹H-NMR(DMSO-d₆):δ 1.38(3H, d, J=5.96 Hz), 1.46(9H, s), 2.36(3H,s), 3.19(2H, t, J=8.16 Hz), 3.87(2H, s), 4.28(2H, t, J=8.16 Hz),4.78-4.83(1H, m), 6.89(1H, d, J=7.76 Hz), 6.98(1H, d, J=6.16 Hz),7.04(1H, s), 7.37(1H, d, J=8.28 Hz), 7.66-7.72(4H, m), 7.98(1H, d,J=8.60 Hz), 9.68(1H, s), 10.06(1H, s)

EXAMPLE 209

[1298] A mixture of tert-butyl6-(2-{5-[(2-isopropoxy-4-methylbenzoyl)amino]-2,3-dihydro-1H-indol-1-yl}-2-oxoethyl)-2-pyridinylcarbamate (1.0 g) and trifluoroacetic acid (1.42 ml) in dichloromethane(5 ml) was stirred at ambient temperature for 5 hours. The reactionmixture was evaporated in vacuo and the residue was dissolved in amixture of ethyl acetate and water and adjusted to pH 8.5 with aqueouspotassium carbonate solution. The organic layer was washed with brineand dried over magnesium sulfate. The solvent was concentrated in vacuoand the residue was recrystallized from ethyl acetate and diisopropylether to giveN-{1-[(6-amino-2-pyridinyl)acetyl]-2,3-dihydro-1H-indol-5-yl}-2-isopropoxy-4-methylbenzamide(757 mg).

[1299]¹H-NMR(DMSO-d₆): δ 1.38 (3H, d, J=5.98 Hz), 2.36 (3H, s), 3.15(2H,t, J=8.38 Hz), 3.71 (2H, s), 4.20 (2H, t, J=8.38 Hz), 4.75-4.86 (1H,m), 5.88 (2H, s), 6.31 (1H, d, J=7.92 Hz), 6.44 (1H, d, J=6.98 Hz), 6.89(1H, d, J=7.76 Hz), 7.03 (1H, s), 7.28-7.40 (2H, m), 7.68-7.74 (2H, m),7.99 (1H, d, J=8.68 Hz), 10.06 (1 H, s) (+)ESI-MS(m/z): 445(M+1)⁺,467(M+Na)⁺

EXAMPLE 210

[1300]N-(1-{[2-(Formylamino)-1,3-thiazol-4-yl]acetyl}-2,3-dihydro-1H-indol-5-yl)-2-isopropoxy-4-methylbenzamide

[1301] The title compound was obtained in a similar manner as in Example208 from (2-(formylamino)-1,3-thiazol-4-yl)acetic acid,1-hydroxybenzotriazole hydrate and1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide.

[1302]¹H-NMR(DMSO-d₆): δ 1.39(3H, d J=6.04 Hz), 2.36(3H, s), 3.17(2H, t,J=8.36 Hz), 3.86(2H, s), 4.20(2H, t, J=8.36 Hz), 4.77-4.83(1H, m),6.89(1H, d, J=7.88 Hz), 7.04(2H, s), 7.37-7.40(1H, m), 7.69-7.82(2H, m),8.00(1H, d, J=8.68 Hz), 8.46(1H, s), 10.06(1H, s)

EXAMPLE 211

[1303] A solution ofN-(1-{[2-(formylamino)-1,3-thiazol-4-yl]acetyl)-2,3-dihydro-1H-indol-5-yl)-2-isopropoxy-4-methylbenzamide(460 mg) and concentrated hydrochloric acid (246 mg) in methanol (30 ml)and tetrahydrofuran (30 ml) was stirred at 50-55° C. for 2 hours. Thereaction mixture was evaporated in vacuo and the residue was dissolvedin a mixture of ethyl acetate and water and adjusted to pH 8.5 withaqueous potassium carbonate solution. The organic layer was washed withbrine and dried over magnesium sulfate. The solvent was concentrated invacuo and the precipitate was collected by filtration to giveN-{1-[{2-amino-1,3-thiazol-4-yl)acetyl]-2,3-dihydro-1H-indol-5-yl}-2-isopropoxy-4-methylbenzamide(350 mg).

[1304]¹H-NMR(DMSO-d₆): δ 1.38(3H, d, J=6.00 Hz), 2.36(3H, s), 3.15(2H,t, J=8.36 Hz), 3.57(2H, s), 4.20(2H, t, J=8.36 Hz), 4.74-4.86(1H, m),6.32(1H, s), 6.87-6.98(3H, m), 7.04(1H, s), 7.38(1H, d, J=8.68 Hz),7.69-7.74(2H, m), 7.99(1H, d, J=8.68 Hz), 10.06(1H, s) (+)ESI-MS(m/z):451(M+1)⁺, 473(M+Na)⁺

EXAMPLE 212

[1305] A mixture ofN-(2,3-dihydro-1H-indol-5-yl)-2-isopropoxy-4-methylbenzamide (291 mg),2-pyridylacetic acid dihydrochloride (417 mg), 1-hydroxybenzotriazolehydrate (241 mg), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide (244mg) and N,N-dimethylaminopyridine (4 mg) in N,N-dimethylformamide (15ml) was stirred at ambient temperature overnight. The reaction mixturewas poured into a mixture of ethyl acetate and water, and the organiclayer was washed with brine and dried over magnesium sulfate. Thesolvent was concentrated in vacuo, and the precipitate was collected byfiltration to give2-isopropoxy-4-methyl-N-[1-(2-pyridinylacetyl)-2,3-dihydro-1H-indol-5-yl]benzamide(635 mg).

[1306]¹H-NMR(DMSO-d₆): δ 1.38(3H, d, J=6.02 Hz), 2.36(3H, s), 3.17(2H,t, J=8.36 Hz), 4.05(2H, s), 4.74-4.86(1H, m), 6.88(1H, d, J=7.76 Hz),7.04(1H, s), 7.25-7.39(3H, m), 7.70-7.81(3H, m), 7.98(1H, d, J=8.68 Hz),8.49-8.52(1H, m), 10.06(1H, s) (+)ESI-MS(m/z): 430(M+1)⁺, 452(M+Na)⁺

EXAMPLE 213

[1307]4-Chloro-2-isopropoxy-N-[1-(2-pyridinylacetyl)-2,3-dihydro-1H-indol-5-yl]benzamide

[1308] The title compound was obtained in a similar manner as in Example212 from 4-chloro-2-isopropoxybenzoic acid, 2-pyridylacetic aciddihydrochloride, 1-hydroxybenzotriazole hydrate and1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide.

[1309]¹H-NMR(DMSO-d₆): δ 1.35(3H, d, J=6.00 Hz), 3.21(2H, t, J=8.36 Hz),4.05(2H, s), 4.22(2H, t, J=8.36 Hz), 4.76-4.88(1H, m), 7.11(1H, dd,J=1.80 Hz, 8.26 Hz), .7.13-7.38(4H, m), 7.68-7.81(3H, m), 7.99(1H, d,J=8.66 Hz), 8.50(1H, d, J=4.56 Hz), 10.02(1H, s) (+)ESI-MS(m/z):450(M+1)⁺, 472(M+Na)⁺

EXAMPLE 214

[1310]2-Isopropoxy-N-[1-(2-pyridinylacetyl)-2,3-dihydro-1H-indol-5-yl]benzamide

[1311] The title compound was obtained in a similar manner as in Example212 from 2-isopropoxybenzoic acid, 2-pyridylacetic acid dihydrochloride,1-hydroxybenzotriazole hydrate and1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide.

[1312]¹H-NMR(DMSO-d₆): δ 1.36(3H, d, J=6.04 Hz), 3.17(2H, t, J=8.36 Hz),4.06(2H, s), 4.22(2H, t, J=8.36 Hz), 4.74-4.80(1H, m), 7.07(1H, d,J=7.48 Hz), 7.19(1H, d, J=8.40 Hz), 7.27-7.29(1H, m), 7.36-7.48(3H, m),7.71-7.77(3H, m), 7.99(1H, d, J=8.64 Hz), 8.50-8.51(1H, m), 10.09(1H, s)

EXAMPLE 215

[1313]2-Methoxy-N-[1-(2-pyridinylacetyl)-2,3-dihydro-1H-indol-5-yl]benzamide

[1314] The title compound was obtained in a similar manner as in Example212 from 2-methoxybenzoic acid, 2-pyridylacetic acid dihydrochloride,1-hydroxybenzotriazole hydrate and1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide.

[1315]¹H-NMR(DMSO-d₆): δ 3.17(2H, t, J=8.36 Hz), 3.90(3H, s), 4.01(2H,s), 4.22(2H, t, J=8.36 Hz), 7.08(1H, d, J=7.60 Hz), 7.17(1H, d, J=8.28Hz), 7.31-7.50(4H, m), 7.62-7.77(3H, m), 7.98(1H, d, J=8.60 Hz),8.50(1H, d, J=5.00 Hz), 10.05(1H, s) (+)ESI-MS(m/z): 388(M+1)⁺,410(M+Na)⁺

EXAMPLE 216

[1316]2-Methoxy-4-methyl-N-[1-(2-pyridinylacetyl)-2,3-dihydro-1H-indol-5-yl]benzamide

[1317] The title compound was obtained in a similar manner as in Example212 from 2-methoxy-4-methylbenzoic acid, 2-pyridylacetic aciddihydrochloride, 1-hydroxybenzotriazole hydrate and1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide.

[1318]¹H-NMR(DMSO-d₆): δ 2.37(3H, s), 3.16(2H, t, J=8.36 Hz), 3.92(3H,s), 3.98(2H, s), 4.22(2H, t, J=8.36 Hz), 6.88(1H, d, J=7.76 Hz),7.01(1H, s), 7.27-7.46(3H, m), 7.61(1H, d, J=7.72 Hz), 7.72-7.77(2H, m),7.98(1H, d, J=8.66 Hz), 8.49-8.51(1H, m), 9.96(1H, s) (+)ESI-MS(m/z):402(M+1)⁺, 424(M+Na)⁺

EXAMPLE 217

[1319]2-Ethoxy-4-methyl-N-[1-(2-pyridinylacetyl)-2,3-dihydro-1H-indol-5-yl]benzamide

[1320] The title compound was obtained in a similar manner as in Example212 from 2-ethoxy-4-methylbenzoic acid, 2-pyridylacetic aciddihydrochloride, 1-hydroxybenzotriazole hydrate and1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide.

[1321]¹H-NMR(DMSO-d₆): δ 1.43(3H, t, J=6.90 Hz), 2.36(3H, s), 3.17(2H,t, J=8.36 Hz), 3.93(2H, s), 4.04-4.26(4H, m), 6.89(1H, d, J=7.92 Hz),7.00(1H, s), 7.25-7.42(3H, m), 7.65-7.80(3H, m), 7.98(1H, d, J=8.66 Hz),8.50(1H, d, J=4.92 Hz), 10.02(1H, s) (+)ESI-MS(m/z): 416(M+1)⁺,438(M+Na)⁺

[1322] Preparation 134

[1323] The following compound was obtained in substantially the samemanner as in Preparation 64.

[1324] 4-Acetyl-2-(dimethylamino)benzoic acid

[1325]¹H-NMR(DMSO-d₆): δ 2.63(3H, s), 2.87(6H, s), 7.73(1H, dd, J=0.9Hz, 8.0 Hz), 7.87-7.97(2H, m), 15.63-17.36(1H, br)(−)ESI-MS(m/z):206(M−H)⁻

EXAMPLE 218

[1326] The following compound was obtained in substantially the samemanner as in Example 74.

[1327]4-Acetyl-2-(dimethylamino)-N-(4-{[2-(2-pyridinyl)ethyl]amino}phenyl)benzamide

[1328]¹H-NMR(DMSO-d₆): δ 2.61(3H, s), 2.83(6H, s), 2.99(2H, t, J=7.1Hz), 3.30-3.44(2H, m), 5.60(1H, t, J=5.7 Hz), 6.59(2H, d, J=8.8 Hz),7.18-7.27(1H, m), 7.32(1H, d, J=7.8 Hz), 7.44(2H, d, J=8.8 Hz),7.55-7.63(2H, m), 7.63-7.77(2H, m), 8.49-8.55(1H, m), 10.58(1H, s)(+)ESI-MS(m/z):403(M+H)⁺, 425(M+Na)⁺

EXAMPLE 219

[1329] The following compound was obtained in substantially the samemanner as in Example 70.

[1330]N-(4-{Formyl[2-(2-pyridinyl)ethyl]amino}phenyl)-4-methyl-2-(methylamino)benzamide

[1331]¹H-NMR(DMSO-d₆): δ 2.30(3H, s), 2.80(3H, d, J=5.0 Hz), 2.91(2H, t,J=7.4 Hz), 4.10(2H, t, J=7.4 Hz), 6.43-6.54(2H, m), 7.17-7.30(4H, m),7.47(1H, q, J=5.0 Hz), 7.57-7.80(4H, m), 8.34(1H, s), 8.44-8.52(1H, m),10.04(1H, s)

EXAMPLE 220

[1332] Acetyl chloride (0.28 mL) was added to a mixture ofN-(4-{formyl[2-(2-pyridinyl)ethyl]amino}phenyl)-4-methyl-2-(methylamino)benzamideand triethylamine (0.54 mL) in tetrahydrofuran (30 mL), and the mixturewas stirred for 1.5 hours at ambient temperature. The reaction mixturewas poured into a mixture of ethyl acetate and saturated sodiumhydrogencarbonate aqueous solution. The separated organic layer waswashed with water, dried over magnesium sulfate and evaporated in vacuo.The residue was triturated with a mixture of isopropyl ether and ether(1:1 v/v) to give2-[acetyl(methyl)amino]-N-(4-{formyl[2-(2-pyridinyl)ethyl]amino}phenyl)-4-methylbenzamide(0.94 g).

[1333]¹H-NMR(DMSO-d₆): δ 1.73(3H, s), 2.40(3H, s), 2.90(2H, t, J=7.4Hz), 3.08(3H, s), 4.10(2H, t, J=7.4 Hz), 7.11-7.40(6H, m), 7.56(1H, d,J=7.7 Hz), 7.62-7.77(3H, m), 8.33(1H, s), 8.44-8.50(1H, m), 10.45(1H, s)(+)ESI-MS(m/z): 431(M+H)⁺, 453(M+Na)⁺

EXAMPLE 221

[1334] The following compound was obtained in substantially the samemanner as in Example 71.

[1335]2-[Acetyl(methyl)amino]-4-methyl-N-(4-{[2-(2-pyridinyl)ethyl]amino}phenyl)benzamide

[1336]¹H-NMR(DMSO-d₆): δ 1.72(3H, s), 2.38(3H, s), 2.98(2H, t, J=7.2Hz), 3.06(3H, s), 7.26-7.44(2H, m), 5.57(1H, t, J=5.6 Hz), 6.57(2H, d,J=8.8 Hz), 7.16-7.43(6H, m), 7.49(1H, d, J=7.8 Hz), 7.71(1H, dt, J=1.7Hz,7.6 Hz), 8.47-8.56(1H, m), 9.93(1H, s) (+)ESI-MS(m/z): 403(M+H)⁺,425(M+Na)⁺

EXAMPLE 222

[1337] The following compound was obtained in substantially the samemanner as in Example 71.

[1338]4-Methyl-2-(methylamino)-N-(4-{[2-(2-pyridinyl)ethyl]amino}phenyl)benzamide

[1339]¹H-NMR(DMSO-d₆): δ 2.28(3H, s), 2.78(3H, d, J=5.0 Hz), 2.98(2H, t,J=7.2 Hz), 3.29-3.43(2H, m), 5.54(1H, t, J=5.7 Hz), 6.38-6.50(2H, m),6.56(2H, d, J=8.8 Hz), 7.18-7.28(1H, m), 7.28-7.38(1H, m), 7.37(2H, d,J=8.8 Hz), 7.46-7.60(2H, m), 7.67-7.76(1H, m), 8.49-8.55(1H, m),9.63(1H, s) (+)ESI-MS(m/z): 361(M+H)⁺, 383(M+Na)⁺

EXAMPLE 223

[1340] The following compound was obtained in substantially the samemanner as in Example 74.

[1341]4-Chloro-2-(methylamino)-N-(4-{[2-(2-pyridinyl)ethyl]amino}phenyl)benzamide

[1342]¹H-NMR(DMSO-d₆): δ 2.78(3H, d, J=4.9 Hz), 2.99(2H, t, J=7.2 Hz),3.30-3.44(2H, m), 5.59(1H, t, J=5.6 Hz), 6.52-6.67(4H, m), 7.17-7.27(1H,m), 7.27-7.46(3H, m), 7.54-7.77(3H, m), 8.48-8.56(1H, m), 9.81(1H, s)(+)ESI-MS(m/z): 381(M+H)⁺, 403(M+Na)⁺

EXAMPLE 224

[1343] The following compound was obtained in substantially the samemanner as in Example 74.

[1344]2-Amino-4-methyl-N-(4-{[2-(2-pyridinyl)ethyl]amino}phenyl)benzamide

[1345]¹H-NMR(DMSO-d₆): δ 2.19(3H, s), 2.98(2H, t, J=7.2 Hz),3.28-3.44(2H, m), 5.53(1H, t, J=5.5 Hz), 6.31(2H, s), 6.38(1H, dd, J=1.1Hz,8.2 Hz), 6.49-6.63(3H, m), 7.18-7.27(1H, m), 7.27-7.43(3H, m),7.51(1H, d, J=8.2 Hz), 7.65-7.77(1H, m), 8.48-8.56(1H, m), 9.56(1H, s)(+)ESI-MS(m/z): 347(M+H)⁺, 369(M+Na)⁺

[1346] Preparation 135

[1347] To a mixture of 2-amino-4,5-dimethoxybenzoic acid (5.0 g) and 37%aqueous formaldehyde (38.1 ml) in methanol (100 ml) was added 10%palladium on carbon (3.0 g, 50% wet). The reaction mixture was stirredat ambient temperature for 7 hours under hydrogen atmosphere. Thecatalyst was filtered off and the solvent was removed by concentration.The residue was purified by column chromatography on silica gel using amixture of chloroform and methanol (9:1 v/v) as an eluant. The elutedfractions containing the desired product were collected and evaporatedin vacuo. The residue was triturated with diethyl ether to give2-(dimethylamino)-4,5-dimethoxybenzoic acid (0.54 g).

[1348]¹H-NMR(DMSO-d₆): δ 2.81(6H, s), 3.80(3H, s), 3.88(3H, s), 7.36(1H,s), 7.46(1H, s) (−)ESI-MS(m/z): 224(M−H)⁻

EXAMPLE 225

[1349] The following compound was obtained in substantially the samemanner as in Example 74.

[1350]2-(Dimethylamino)-4,5-dimethoxy-N-(4-{[2-(2-pyridinyl)ethyl]amino}phenyl)benzamide

[1351]¹H-NMR(DMSO-d₆): δ 2.75(6H, s), 2.99(2H, t, J=7.2 Hz),3.30-3.46(2H, m), 3.79(3H, s), 3.86(3H, s), 5.56(1H, t, J=5.7 Hz),6.61(2H, d, J=8.7 Hz), 7.03(1H, s), 7.18-7.28(1H, m), 7.32(1H, d, J=7.7Hz), 7.45(2H, d, J=8.7 Hz), 7.57(1H, s), 7.71(1H, dt, J=1.8 Hz,7.7 Hz),8.49-8.56(1H, m), 12.35(1H, s) (+)ESI-MS(m/z): 421(M+H)⁺, 443(M+Na)⁺

[1352] Preparation 136

[1353] The following compound was obtained in substantially the samemanner as in Preparation 73.

[1354] Methyl 1-methyl-1,2,3,4-tetrahydro-8-quinolinecarboxylate

[1355]¹H-NMR(DMSO-d₆): δ 2.76-2.90(2H, m), 2.68(2H, t, J=6.2 Hz),2.72(3H, s), 3.19(2H, t, J=5.8 Hz), 3.77(3H, s), 6.56(1H, t, J=7.6 Hz),7.03(1H, dd, J=1.8 Hz,7.6 Hz), 7.27(1H, dd, J=1.8 Hz,7.6 Hz)

[1356] Preparation 137

[1357] The following compound was obtained in substantially the samemanner as in Preparation 64.

[1358] 1-Methyl-1,2,3,4-tetrahydro-8-quinolinecarboxylic acid

[1359]¹H-NMR(DMSO-d₆): δ 1.78-1.94(2H, m), 2.71(2H, t, J=6.3 Hz),2.76(3H, s), 3.18(2H, t, J=5.8 Hz), 6.69(1H, t, J=7.5 Hz), 7.07(1H, d,J=7.5 Hz), 7.39(1H, d, J=7.5 Hz), 13.16(1H, s) (−)ESI-MS(m/z): 190(M−H)⁻

EXAMPLE 226

[1360] The following compound was obtained in substantially the samemanner as in Example 74.

[1361]1-Methyl-N-(4-{[2-(2-pyridinyl)ethyl]amino}phenyl)-1,2,3,4-tetrahydro-8-quinolinecarboxamide

[1362]¹H-NMR(DMSO-d₆): δ 1.76-1.93(2H, m), 2.73(2H, t, J=6.1 Hz),2.77(3H, s), 2.98(2H, t, J=7.2 Hz), 3.01-3.23(2H, m), 3.28-3.44(2H, m),5.55(1H, t, J=5.7 Hz), 6.58(2H, d, J=8.8 Hz), 6.75(1H, t, J=7.5 Hz),7.00-7.08(1H, m), 7.18-7.37(3H, m), 7.42(2H, d, J=8.8 Hz), 7.71(1H, dt,J=1.7 Hz, 7.6 Hz), 8.48-8.55(1H, m), 10.09(1H, s) (+)ESI-MS(m/z):387(M+H)⁺, 409(M+Na)⁺

[1363] Preparation 138

[1364] The following compound was obtained in substantially the samemanner as in Preparation 73.

[1365] Methyl 1-ethyl-1,2,3,4-tetrahydro-8-quinolinecarboxylate

[1366]¹H-NMR(DMSO-d₆): δ 1.06(3H, t, J=7.0 Hz), 1.71-1.86(2H, m),2.69(2H, t, J=6.2 Hz), 2.98(2H, q, J=7.0 Hz), 3.07-3.16(2H, m), 3.77(3H,s), 6.64(1H, t, J=7.6 Hz), 7.05(1H, dd, J=1.7 Hz,7.6 Hz), 2.77(1H, dd,J=1.7 Hz, 7.6 Hz)

[1367] Preparation 139

[1368] The following compound was obtained in substantially the samemanner as in Preparation 64.

[1369] 1-Ethyl-1,2,3,4-tetrahydro-8-quinolinecarboxylic acid

[1370]¹H-NMR(DMSO-d₆): δ 1.12(3H, t, J=7.1 Hz), 1.77-1.93(2H, m),2.77(2H, t, J=6.6 Hz), 3.00(2H, q, J=7.1 Hz), 3.15(2H, t, J=5.7 Hz),6.88(1H, t, J=7.5 Hz), 7.13-7.20(1H, m), 7.42-7.50(1H, m), 14.11(1H, s)(−)ESI-MS(m/z): 204(M−H)⁻

EXAMPLE 227

[1371] The following compound was obtained in substantially the samemanner as in Example 74.

[1372]1-Ethyl-N-(4-{[2-(2-pyridinyl)ethyl]amino}phenyl)-1,2,3,4-tetrahydro-8-quinolinecarboxamide

[1373]¹H-NMR(DMSO-d₆): δ 1.00(3H, t, J=7.0 Hz), 1.70-1.87(2H, m),2.75(2H, t, J=6.3 Hz), 2.92-3.09(4H, m), 3.09-3.19(2H, m), 3.36(2H, t,J=7.2 Hz), 5.55(1H, s), 6.58(2H, d, J=8.8 Hz), 6.82(1H, t, J=7.5 Hz),7.01-7.10(1H, m), 7.17-7.36(3H, m), 7.44(2H, d, J=8.8 Hz), 7.65-7.76(1H,m), 8.48-8.55(1H, m), 10.13(1H, s) (+)ESI-MS(m/z): 401(M+H)⁺, 423(M+Na)⁺

[1374] Preparation 140

[1375] The following compound was obtained in substantially the samemanner as in Preparation 73.

[1376] Methyl5-chloro-1-methyl-1,2,3,4-tetrahydro-8-quinolinecarboxylate

[1377]¹H-NMR(DMSO-d₆): δ 1.78-1.93(2H, m), 2.72(2H, t, J=6.8 Hz),2.73(3H, s), 3.20(2H, t, J=5.7 Hz), 3.79(3H, s), 6.71(1H, d, J=8.5 Hz),7.30(1H, d, J=8.5 Hz)

[1378] Preparation 141

[1379] The following compound was obtained in substantially the samemanner as in Preparation 64.

[1380] 5-Chloro-1-methyl-1,2,3,4-tetrahydro-8-quinolinecarboxylic acid

[1381]¹H-NMR(DMSO-d₆): δ 1.78-1.94(2H, m), 2.72(2H, t, J=6.3 Hz),2.78(3H, s), 3.20(2H, t, J=5.6 Hz), 6.75(1H, d, J=8.4 Hz), 7.37(1H, d,J=8.4 Hz), 12.87(1H, s) (−)ESI-MS(m/z): 224(M−H)⁻

EXAMPLE 228

[1382] The following compound was obtained in substantially the samemanner as in Preparation 74.

[1383]5-Chloro-1-methyl-N-(4-{[2-(2-pyridinyl)ethyl]amino}phenyl)-1,2,3,4-tetrahydro-8-quinolinecarboxamide

[1384]¹H-NMR(DMSO-d₆): δ 1.78-1.96(2H, m), 2.74(2H, t, J=6.4 Hz),2.80(3H, s), 2.98(2H, t, J=7.0 Hz), 3.12-3.22(2H, m), 3.29-3.43(2H, m),5.57(1H, s), 6.58(2H, d, J=8.8 Hz), 6.89(1H, d, J=8.3 Hz), 7.18-7.37(3H,m), 7.40(2H, d, J=8.8 Hz), 7.71(1H, dt, J=1.8 Hz,7.6 Hz), 8.49-8.56(1H,m), 10.00(1H, s) (+)ESI-MS(m/z): 421(M+H)⁺, 443(M+Na)⁺

EXAMPLE 229

[1385] The following compound was obtained in substantially the samemanner as in Preparation 74.

[1386] N-(4-{[2-(2-Pyridinyl)ethyl]amino}phenyl)-8-quinolinecarboxamide

[1387]¹H-NMR(DMSO-d₆): δ 3.02(2H, t, J=7.2 Hz), 3.32-3.49(2H, m),5.66(1H, t, J=5.7 Hz), 6.66(2H, d, J=8.8 Hz), 7.19-7.29(1H, m), 7.34(1H,d, J=7.8 Hz), 7.63(2H, d, J=8.8 Hz), 7.67-7.87(3H, m), 8.24(1H, dd,J=1.3 Hz,8.1 Hz), 8.50-8.72(3H, m), 9.10-9.21(1H, m), 12.96(1H, s)(+)ESI-MS(m/z): 369(M+H)⁺, 391(M+Na)⁺

[1388] Preparation 142

[1389] The following compound was obtained in substantially the samemanner as in Preparation 90.

[1390] Benzyl 6-methyl-2-(1-piperidinyl)nicotinate

[1391]¹H-NMR(DMSO-d₆): δ 1.51 (6H, s), 2.34 (3H, s), 3.24-3.27 (4H, m),5.28 (2H, s), 6.63 (1H, d, J=7.7 Hz), 7.30-7.48 (5H, m), 7.82 (1H, d,J=7.7 Hz)

[1392] Preparation 143

[1393] The following compound was obtained in substantially the samemanner as in Preparation 91.

[1394] 6-Methyl-2-(1-piperidinyl)nicotinic acid

[1395]¹H-NMR(DMSO-d₆): δ 1.59 (6H, s), 2.38 (3H, s), 3.25 (4H, s), 6.78(1H, d, J=7.7 Hz), 7.87 (1H, d, J=7.7 Hz)

[1396] Preparation 144

[1397] The following compound was obtained in substantially the samemanner as in Preparation 90.

[1398] Benzyl 2-[ethyl(methyl)amino]-6-methylnicotinate

[1399]¹H-NMR(DMSO-d₆): δ 1.16 (3H, t, J=7.0 Hz), 2.38 (3H, s), 2.84 (3H,s), 3.54 (2H, q, J=7.0 Hz), 5.29 (2H, s), 6.44 (1H, d, J=7.7 Hz),7.23-7.45 (5H, m), 7.82 (1H, d, J=7.7 Hz)

[1400] Preparation 145

[1401] The following compound was obtained in substantially the samemanner as in Preparation 91.

[1402] 2-[Ethyl(methyl)amino]-6-methylnicotinic acid

[1403]¹H-NMR(DMSO-d₆): δ 1.10 (3H, t, J=7.0 Hz), 2.35 (3H, s), 2.83 (3H,s), 3.45 (2H, q, J=7.0 Hz), 6.61 (1H, d, J=7.7 Hz), 7.79 (1H, d, J=7.7Hz)

[1404] Preparation 146

[1405] The following compound was obtained in substantially the samemanner as in Preparation 90.

[1406] Benzyl 2-(diethylamino)-6-methylnicotinate

[1407]¹H-NMR(DMSO-d₆): δ 1.03 (6H, t, J=7.0 Hz), 2.33 (3H, s), 3.31 (4H,q, J=7.0 Hz), 5.27 (2H, s), 6.55 (1H, d, J=7.7 Hz), 7.30-7.48 (5H, m),7.72 (1H, d, J=7.7 Hz)

[1408] Preparation 147

[1409] The following compound was obtained in substantially the samemanner as in Preparation 91.

[1410] 2-(Diethylamino)-6-methylnicotinic acid

[1411]¹H-NMR(DMSO-d₆): δ 1.02 (6H, t, J=7.0 Hz), 2.42 (3H, s), 3.33 (4H,q, J=7.0 Hz), 6.88 (1H, d, J=7.7 Hz), 7.92 (1H, d, J=7.7 Hz)

[1412] Preparation 148

[1413] The following compound was obtained in substantially the samemanner as in Preparation 90.

[1414] Benzyl 6-methyl-2-(methylamino)nicotinate

[1415]¹H-NMR(DMSO-d₆): δ 2.39 (3H, s), 3.06 (3H, d, J=4.8 Hz), 5.30 (2H,s), 6.35 (1H, d, J=7.9 Hz), 7.32-7.44 (5H, m), 7.88 (1H, m), 8.02 (1H,d, J=7.9 Hz)

[1416] Preparation 149

[1417] The following compound was obtained in substantially the samemanner as in Preparation 91.

[1418] 6-Methyl-2-(methylamino)nicotinic acid

[1419]¹H-NMR(DMSO-d₆): δ 2.34 (3H, s), 2.94 (3H, s), 6.43 (1H, d, J=7.8Hz), 7.92 (1H, d, J=7.8 Hz), 7.92-7.95 (1H, m)

[1420] Preparation 150

[1421] The following compound was obtained in substantially the samemanner as in Preparation 90.

[1422] Benzyl 2-(isopropylamino)-6-methylnicotinate

[1423]¹H-NMR(DMSO-d₆): δ 1.24 (6H, d, J=6.5 Hz), 2.39 (3H, s), 4.33-4.67(1H, m), 5.27 (2H, s), 6.32 (1H, d, J=7.9 Hz), 7.24 -7.74 (5H, m), 7.80(1H, d, J=6.8 Hz), 8.01 (1H, d, J=7.9 Hz)

[1424] Preparation 151

[1425] The following compound was obtained in substantially the samemanner as in Preparation 91.

[1426] 2-(Isopropylamino)-6-methylnicotinic acid

[1427]¹H-NMR(DMSO-d₆): δ 1.24 (6H, d, J=6.4 Hz), 2.37 (3H, s), 4.36-4.49(1H, m), 6.31 (1H, d, J=7.7 Hz), 8.13 (1H, d, J=7.7 Hz)

[1428] Preparation 152

[1429] The following compound was obtained in substantially the samemanner as in Preparation 90.

[1430] Benzyl 2-(cyclohexylamino)-6-methylnicotinate

[1431]¹H-NMR(DMSO-d₆): δ 1.25-1.48 (6H, m), 1.68-1.78 (2H, m), 1.98-2.05(2H, m), 4.08-4.19 (1H, m), 5.27 (2H, s), 6.30 (1H, d, J=7.9 Hz),7.22-7.42 (5H, m), 7.92 (1H, d, J=7.5 Hz), 8.00 (1H, d, J=7.9 Hz)

[1432] Preparation 153

[1433] The following compound was obtained in substantially the samemanner as in Preparation 91.

[1434] 2-(Cyclohexylamino)-6-methylnicotinic acid

[1435]¹H-NMR(DMSO-d₆): δ 1.05-1.41 (6H, m), 1.55-1.69 (2H, m), 1.89-1.99(2H, m), 2.31 (3H, s), 3.98-4.09 (1H, m), 6.40 (1H, d, J=7.9 Hz), 7.92(1H, d, J=7.9 Hz), 8.17 (1H, d, J=7.2 Hz)

EXAMPLE 230

[1436] The following compound was obtained in substantially the samemanner as in Preparation 52.

[1437] tert-Butyl[4-({[6-methyl-2-(methylamino)-3-pyridinyl]carbonyl}amino)phenyl][2-(2-pyridinyl)ethyl]carbamate

[1438]¹H-NMR(DMSO-d₆): δ 1.33 (9H, s), 2.36 (3H, s), 2.87-2.93 (5H, m),3.88-3.95 (2H, m), 6.50 (1H, d, J=7.8 Hz), 7.14 -7.26 (4H, m), 7.63-7.73(3H, m), 7.96-8.00 (2H, m), 8.45-8.47 (1H, m), 10.09 (1H, s)

EXAMPLE 231

[1439] The following compound was obtained in substantially the samemanner as in Example 44.

[1440]6-Methyl-2-(methylamino)-N-(4-{[2-(2-pyridinyl)ethyl]amino}phenyl)nicotinamide

[1441]¹H-NMR(DMSO-d₆): δ 2.34 (3H, s), 2.90 (3H, d, J=4.7 Hz), 2.91-3.02(2H, m), 3.32-3.42 (2H, m), 5.58 (1H, t, J=5.7 Hz), 6.46 (1H, d, J=7.8Hz), 6.57 (2H, d, J=8.9 Hz), 7.19-7.30 (2H, m), 7.36 (2H, d, J=8.9 Hz),7.67-7.75 (1H, m), 7.93 (1H, d, J=7.8 Hz), 8.06-8.09(1H, m), 8.51-8.53(1H, m), 9.74 (1H, s) ESI-MS(m/z): 384(M+Na)⁺, 362(M+H)⁺

EXAMPLE 232

[1442] The following compound was obtained in substantially the samemanner as in Example 91.

[1443]2-(Cyclohexylamino)-N-(4-{formyl[2-(2-pyridinyl)ethyl]amino}phenyl)-6-methylnicotinamide

[1444]¹H-NMR(DMSO-d₆): δ 1.27-1.46 (6H, m), 1.55-1.64 (2H, m), 1.89-1.99(2H, m), 2.34 (3H, s), 2.74-2.95 (2H, m), 4.01-4.15 (3H, m), 6.49 (1H,d, J=7.9 Hz), 7.18-7.31 (4H, m), 7.64-7.73 (3H, m), 7.96-8.03 (1H, m),8.22 (1H, d, J=7.6 Hz), 8.35 (1H, s), 8.46-8.49 (1H, m), 10.12 (1H, s)

EXAMPLE 233

[1445] The following compound was obtained in substantially the samemanner as in Example 92.

[1446]2-(Cyclohexylamino)-6-methyl-N-(4-{[2-(2-pyridinyl)ethyl]amino}phenyl)nicotinamide

[1447]¹H-NMR(DMSO-d₆): δ 1.40-1.64 (8H, m), 1.88-1.99 (2H, m), 2.32 (3H,s), 2.99 (2H, t, J=7.4 Hz), 3.32-3.42 (2H, m), 3.98-4.01 (1H, m), 5.59(1H, t, J=5.7 Hz), 6.43 (1H, d, J=7.8 Hz), 6.58 (2H, d, J=8.8 Hz),7.20-7.35 (4H, m), 7.67-7.75 (1H, m), 7.94 (1H, d, J=7.8 Hz), 8.30 (1H,d, J=7.6 Hz), 8.51-8.53 (1H, m), 9.73 (1H, s) ESI-MS(m/z): 452(M+Na)⁺,430(M+H)⁺

EXAMPLE 234

[1448] The following compound was obtained in substantially the samemanner as in Example 43.

[1449] tert-Butyl[4-({[2-(isopropylamino)-6-methyl-3-pyridinyl]carbonyl}amino)phenyl][2-(2-pyridinyl)ethyl]carbamate

[1450]¹H-NMR(DMSO-d₆): δ 1.24 (6H, d, J=6.7 Hz), 1.33 (9H, s), 2.35 (3H,s), 2.90 (2H, t, J=7.4 Hz), 3.92 (2H, t, J=7.4 Hz), 4.22-4.32 (1H, m),6.49 (1H, d, J=7.9 Hz), 7.14-7.26 (4H, m), 7.61-7.74 (3H, m), 7.98-8.07(2H, m), 8.45-8.48 (1H, m), 10.08 (1H, s)

EXAMPLE 235

[1451] The following compound was obtained in substantially the samemanner as in Example 44.

[1452]2-(Isopropylamino)-6-methyl-N-(4-{[2-(2-pyridinyl)ethyl]amino}phenyl)nicotinamide

[1453]¹H-NMR(DMSO-d₆): δ 1.16 (6H, d, J=6.4 Hz), 2.33 (3H, s), 2.99 (2H,t, J=7.4 Hz), 3.33-3.41 (2H, m), 4.15-4.32 (1H, m), 5.62 (1H, br.s),6.44 (1H, d, J=7.7 Hz), 6.57 (2H, d, J=8.8 Hz), 7.19-7.36(4H, m),7.67-7.77 (1H, m), 7.94 (1H, d, J=7.9 Hz), 8.14 (1H, d, J=7.3 Hz),8.51-8.53 (1H, m), 9.73 (1H, s) ESI-MS(m/z): 412(M+Na)⁺, 390(M+H)⁺

EXAMPLE 236

[1454] The following compound was obtained in substantially the samemanner as in Example 43.

[1455] tert-Butyl[4-({[6-methyl-2-(1,3-thiazolidin-3-yl)-3-pyridinyl]carbonyl}amino)phenyl][2-(2-pyridinyl)ethyl]carbamate

[1456]¹H-NMR(DMSO-d₆): δ 1.36 (9H, s), 2.40 (3H, s), 2.69-3.10 (4H, m),3.75 (2H, t, J=6.2 Hz), 3.87-3.94 (2H, m), 4.56 (2H, s), 6.79 (1H, d,J=7.6 Hz), 7.15-7.26 (4H, m), 7.64-7.74 (4H, m), 8.45-8.48 (1H, m),10.40 (1H, s)

EXAMPLE 237

[1457] The following compound was obtained in substantially the samemanner as in Example 44.

[1458]6-Methyl-N-(4-{[2-(2-pyridinyl)ethyl]amino}phenyl)-2-(1,3-thiazolidin-3-yl)nicotinamide

[1459]¹H-NMR(DMSO-d₆): δ 2.78 (3H, s), 2.95-3.02 (4H, m), 3.34-3.40 (2H,m), 3.72-3.78 (2H, m), 4.55 (2H, s), 5.57 (1H, br.s), 6.57 (2H, d, J=8.7Hz), 6.76 (1H, d, J=7.6 Hz), 7.18-7.25 (1H, m), 7.31 (1H, d, J=7.8 Hz),7.40 (2H, d, J=8.7 Hz), 7.62-7.75 (2H, m), 8.51 (1H, d, J=4.2 Hz), 9.97(1H, s) ESI-MS(m/z):442(M+Na)⁺, 420(M+H)⁺

EXAMPLE 238

[1460] A mixture of 1-methyl-1,2,3,4-tetrahydro-8-quinolinecarboxylicacid (230 mg), 2-(4-aminophenyl)-N-(2-pyridinyl)acetamide (284mg),1-hydroxybenzotriazole (170 mg) and1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide (196 mg) inN,N-dimethylformamide (10 ml) was stirred at ambient temperature for 15hours. The reaction mixture was poured into a mixture of ethyl acetateand water and the organic layer was washed with brine and dried overmagnesium sulfate. The solvent was evaporated in vacuo, and the residuewas chromatographed on silica gel eluting with ethyl acetate: n-hexane(7:3 v/v). The eluted fractions containing the desired product werecollected and the solvent was evaporated in vacuo and the residue wascrystallized from a mixture of ethyl acetate and diisopropyl ether togive1-methyl-N-{4-[2-oxo-2-(2-pyridinylamino)ethyl]phenyl}-1,2,3,4-tetrahydro-8-quinolinecarboxamide(153 mg).

[1461]¹H-NMR(DMSO-d₆): δ 1.82-1.87 (2H, m), 2.70-2.76 (2H, m), 2.76 (3H,s), 3.15-3.20 (2H, m), 3.68 (2H, s), 6.71-6.79 (1H, m), 7.05-7.12 (2H,m), 7.24 (1H, d, J=1.2 Hz), 7.30 (2H, d, J=8.4 Hz), 7.66 (2H, d, J=8.4Hz), 7.71-7.80 (1H, m), 8.05 (1H, d, J=8.4 Hz), 8.31-8.33 (1H, m), 10.46(1H, s), 10.67 (1H, s) ESI-MS(m/z): 423(M+Na)⁺, 401(M+H)⁺

EXAMPLE 239

[1462] The following compound was obtained in substantially the samemanner as in Example 238.

[1463]1-Methyl-N-(4-{[(2-pyridinylcarbonyl)amino]methyl}phenyl)-1,2,3,4-tetrahydro-8-quinolinecarboxamide

[1464]¹H-NMR(DMSO-d₆): δ 1.81-1.90 (2H, m), 2.73 (3H, s), 2.70-2.75 (2H,m), 3.14-3.19 (2H, m), 4.45 (2H, d, J=6.3 Hz), 6.71-6.78 (1H, d, J=6.6Hz), 7.23-7.32 (3H, m), 7.78-7.67 (3H, m), 7.96-8.08 (2H, m), 8.65 (1H,d, J=4.7 Hz), 9.30 (1H, t, J=6.3 Hz), 10.40 (1H, s)ESI-MS(m/z):423(M+Na)⁺, 401(M+H)⁺

EXAMPLE 240

[1465] The following compound was obtained in substantially the samemanner as in Example 120.

[1466]1-Methyl-N-{4-[2-(1-pyrazol-1-yl)ethoxy]phenyl}-1,2,3,4-tetrahydro-8-quinolinecarboxamide

[1467]¹H-NMR(DMSO-d₆): δ 1.78-1.90 (2H, m), 2.69-2.76 (2H, m), 2.76 (3H,s), 3.16 (2H, t, J=5.4 Hz), 4.30 (2H, t, J=5.3 Hz), 4.48 (2H, t, J=5.3Hz), 6.24-6.26 (1H, m), 6.70-6.78 (1H m), 6.85 (2H, d, J=9.0 Hz),7.03-7.07 (1H, m),7.23-7.27 (1H, m), 7.46 (1H, d, J=2.0 Hz), 7.61 (2H,d, J=9.0 Hz), 7.78 (1H, d, J=2.0 Hz), 10.28 (1H, s) ESI-MS(m/z):377(M+H)⁺

EXAMPLE 241

[1468] The following compound was obtained in substantially the samemanner as in Example 120.

[1469]2-Isopropoxy-4-methyl-N-{4-[2-(1H-pyrazol-1-yl)ethoxy]phenyl}benzamide

[1470]¹H-NMR(DMSO-d₆): δ 1.38 (6H, d, J=6.0 Hz), 2.35 (3H, s), 4.31 (2H,t, J=5.3 Hz), 4.49 (2H, t, J=5.3 Hz), 4.73-4.85 (1H, m), 6.24-6.26 (1H,m), 6.86-6.94 (3H, m), 7.03 (1H, s), 7.46 (1H, d, J=1.9 Hz), 7.60 (2H,d, J=9.0 Hz), 7.71 (1H, d, J=7.9 Hz), 7.78 (1H, d, J=1.9 Hz), 9.99 (1H,s) ESI-MS(m/z): 380(M+H)⁺

EXAMPLE 242

[1471] The following compound was obtained in substantially the samemanner as in Example 123.

[1472]2-Isopropoxy-4-methyl-N-{4-([2-(1H-1,2,4-triazol-1-yl)ethyl]amino}phenyl)benzamide

[1473]¹H-NMR(DMSO-d₆): δ 1.39 (6H, d, J=6.0 Hz), 2.35 (3H, s), 3.41-3.50(2H, m),4.33 (2H, t, J=6.2 Hz), 4.75-4.84 (1H, m), 5.63-5.66 (1H, m),6.58 (2H, d, J=8.8 Hz), 6.88 (1H, d, J=8.2 Hz), 7.03 (1H, s), 7.42 (2H,d, J=8.8 Hz), 7.74 (2H, d, J=8.2 Hz), 7.99 (1H, s), 8.47 (1H, s), 9.84(1H, s) ESI-MS(m/z): 402(M+Na)⁺, 380(M+H)⁺

EXAMPLE 243

[1474] A mixture of tert-butyl4-{[(2-chloro-6-methyl-3-pyridinyl)carbonyl]amino}phenyl[2-(2-pyridinyl)ethyl]carbamate(467 mg) and sodium isopropoxide (328 mg) in isopropanol (10 ml) wasrefluxed under stirring for 4 hours. The reaction mixture was evaporatedin vacuo and the residue was dissolved in a mixture of ethyl acetate andwater, and the organic layer was washed with brine and dried overmagnesium sulfate. The solvent was evaporated in vacuo and the residuewas chromatographed on silica gel eluting with ethyl acetate: n-hexane(7:3 v/v). The eluted fractions containing the desired product werecollected and evaporated in vacuo to give tert-butyl4-{[(2-isopropoxy-6-methyl-3-pyridinyl)carbonyl]amino}phenyl[2-(2-pyridinyl)ethyl]carbamate(345 mg).

[1475]¹H-NMR(DMSO-d₆): δ 1.33 (9H, s), 1.42 (2H, d, J=6.2 Hz), 2.46 (3H,s), 2.90 (2H, t, J=7.4 Hz), 3.92 (2H, t, J=7.4 Hz), 5.37-5.49 (1H, m),6.99 (1H, d, J=7.7 Hz), 7.17-7.26 (4H, m), 7.64-7.74 (3H, m), 8.07 (1H,d, J=7.6 Hz), 8.45-8.48 (1H, m), 10.09 (1H, s)

EXAMPLE 244

[1476] The following compound was obtained in substantially the samemanner as in Example 44.

[1477]2-Isopropoxy-6-methyl-N-(4-{[2-(2-pyridinyl)ethyl]amino}phenyl)nicotinamide

[1478]¹H-NMR(DMSO-d₆): δ 1.42 (6H, d, J=7.3 Hz), 2.45 (3H, s), 2.99 (2H,t, J=7.4 Hz), 3.34-3.42 (2H, m), 5.38-5.50 (1H, m), 5.64 (1H, br.s),6.61 (2H, d, J=8.8 Hz), 6.98 (1H, d, J=7.6 Hz), 7.39-7.23 (1H, m), 7.32(1H, d, J=7.8 Hz), 7.43 (2H, d, J=8.8 Hz), 7.67-7.76 (1H, m), 8.11 (1H,d, J=7.6 Hz), 8.51-8.53 (1H, m), 9.77 (1H, s) ESI-MS(m/z):413(M+Na)⁺,391(M+H)⁺

EXAMPLE 245

[1479] A mixture of2,6-dichloro-N-(4-{formyl[2-(2-pyridinyl)ethyl]amino}phenyl)nicotinamide(623 mg) and sodium isopropoxide (984 mg) in isopropanol (20 ml) wasrefluxed under stirring for 9 hours. The reaction mixture was evaporatedin vacuo and the residue was dissolved in a mixture of ethyl acetate andwater, and the organic layer was washed with brine and dried overmagnesium sulfate. The solvent was evaporated in vacuo and the residuewas chromatographed on silica gel eluting with ethyl acetate: n-hexane(7:3 v/v). The eluted fractions containing the desired product werecollected and evaporated in vacuo. The residue was crystallized from amixture of diisopropyl ether and n-hexane to give2,6-diisopropoxy-N-(4-{[2-(2-pyridinyl)ethyl]amino}phenyl)nicotinamide(310 mg).

[1480]¹H-NMR(DMSO-d₆): δ 1.35 (6H, d, J=6.2 Hz), 1.47 (6H, d, J=6.2 Hz),3.00 (2H, t, J=7.3 Hz), 3.34-3.44 (2H, m), 5.21-5.59 (2H, m), 5.62 (1H,t, J=5.8 Hz), 6.45 (1H, d, J=8.3 Hz), 6.63 (2H, d, J=8.8 Hz), 7.19-7.26(1H, m), 7.32 (1H, d, J=7.7 Hz), 7.43 (2H, d, J=8.8 Hz), 7.67-7.76 (1H,m), 8.19 (1H, d, J=8.3 Hz), 8.52-8.55 (1H, m), 9.63 (1H, s)ESI-MS(m/z):457(M+Na)⁺, 435(M+H)⁺

EXAMPLE 246

[1481] A mixture of2-chloro-N-(4-{formyl[2-(2-pyridinyl)ethyl]amino}phenyl)-6-methylnicotinamide(632 mg), 2-propanethiol (366 mg) and potassium tert-butoxide (539 mg)in N,N-dimethylformamide (15 ml) was stirred at ambient temperature for8 hours. The reaction mixture was poured into a mixture of ethyl acetateand water, and the organic layer was washed with brine and dried overmagnesium sulfate. The solvent was evaporated in vacuo and the residuewas chromatographed on silica gel eluting with ethyl acetate. The elutedfractions containing the desired product was collected and evaporated invacuo to giveN-(4-{formyl[2-(2-pyridinyl)ethyl]amino}phenyl)-2-(isopropylthio)-6-methylnicotinamide(510 mg).

[1482]¹H-NMR(DMSO-d₆): δ 1.33 (6H, d, J=6.9 Hz), 2.51 (3H, s), 2.92 (2H,t, J=7.3 Hz), 3.95-4.16 (3H, m), 7.09 (1H, d, J=7.8 Hz), 7.21-7.23 (4H,m), 7.64-7.80 (4H, m), 7.96 (1H, s), 8.35 (1H, s), 8.46-8.49 (1H, m),10.44 (1H, s)

EXAMPLE 247

[1483] The following compound was obtained in substantially the samemanner as in Example 92.

[1484]2-(Isopropylthio)-6-methyl-N-(4-{[2-(2-pyridinyl)ethyl]amino}phenyl)nicotinamide

[1485]¹H-NMR(DMSO-d₆): δ 1.31 (6H, d, J=6.8 Hz), 2.49 (3H, s), 2.99 (2H,t, J=7.3 Hz), 3.32-3.42 (2H, m), 3.93-4.08 (1H, m), 5.58 (1H, t, J=5.7Hz), 6.58 (2H, d, J=8.8 Hz), 7.04 (1H, d, J=7.8 Hz), 7.21-7.25 (1H, m),7.31 (1H, d, J=7.8 Hz), 7.42 (2H, d, J=8.8 Hz), 7.66-7.75 (2H, m), 8.52(1H, d, J=4.6 Hz), 9.94 (1H, s) ESI-MS(m/z): 429(M+Na)⁺, 407(M+H)⁺

EXAMPLE 248

[1486] The following compound was obtained in substantially the samemanner as in Example 246.

[1487]N-(4-{Formyl[2-(2-pyridinyl)ethyl]amino}phenyl)-6-methyl-2-(propylthio)nicotinamide

[1488]¹H-NMR(DMSO-d₆): δ 0.97 (3H, t, J=7.3 Hz), 1.60-1.70 (2H, m), 2.51(3H, s), 2.92 (2H, t, J=7.7 Hz), 3.12 (2H, t, J=7.0 Hz), 4.13 (2H, t,J=7.3 Hz), 7.10 (1H, d, J=7.8 Hz), 7.21-7.31 (4H, m), 7.68-7.82 (4H, m),7.96 (1H, s), 8.47-8.50 (1H, m), 10.45 (1H, s)

EXAMPLE 249

[1489] The following compound was obtained in substantially the samemanner as in Example 92.

[1490]6-Methyl-2-(propylthio)-N-(4-{[2-(2-pyridinyl)ethyl]amino}phenyl)nicotinamide

[1491]¹H-NMR(DMSO-d₆): δ 0.96 (3H, t, J=7.2 Hz), 1.54-1.72 (2H, m), 2.48(3H, s), 2.99 (2H, t, J=7.4 Hz), 3.07 (2H, t, J=7.0 Hz), 3.32-3.42 (2H,m), 5.59 (1H, t, J=5.7 Hz), 6.58 (2H, , J=8.8 Hz), 7.05 (1H, d, J=7.8Hz), 7.19-7.26 (1H, m), 7.31 (1H, d, J=7.7 Hz), 7.42 (2H, d, J=8.8 Hz),7.66-7.75 (2H, m), 8.51 (1H, d, J=4.5 Hz), 9.95 (1H, s) ESI-MS(m/z):429(M+Na)⁺, 407(M+H)⁺

EXAMPLE 250

[1492] A mixture of tert-butyl4-{[(2-chloro-6-methyl-3-pyridinyl)carbonyl]amino}phenyl[2-(2-pyridinyl)ethyl]carbamate(560 mg) and sodium thiomethoxide (252 mg) in N,N-dimethylformamide (15ml) was stirred at ambient temperature for 15 hours. The reactionmixture was poured into a mixture of ethyl acetate and water, and theorganic layer was washed with brine and dried over magnesium sulfate.The solvent was evaporated in vacuo to give tert-butyl4-({[6-methyl-2-(methylthio)-3-pyridinyl]carbonyl)amino)phenyl[2-(2-pyridinyl)ethyl]carbamate(550 mg).

[1493]¹H-NMR(DMSO-d₆): δ 1.30 (9H, s), 2.46 (3H, s), 2.89 (3H, s),2.84-2.94 (2H, m), 3.92 (2H, t, J=7.3 Hz), 7.11 (1H, d, J=7.8 Hz),7.16-7.26 (3H, m), 7.65-7.74 (3H, m), 7.83 (1H, d, J=7.8 Hz), 7.96 (1H,s), 8.46-8.48 (1H, m), 10.39 (1H, s)

EXAMPLE 251

[1494] The following compound was obtained in substantially the samemanner as in Example 44.

[1495]6-Methyl-2-(methylthio)-N-(4-{[2-(2-pyridinyl)ethyl]amino}phenyl)nicotinamide

[1496]¹H-NMR(DMSO-d₆): δ 2.44 (3H, s), 2.50 (3H, s), 2.99 (2H, t, J=7.3Hz), 3.34-3.42 (2H, m), 5.59 (1H, t, J=5.7 Hz), 6.58 (2H, d, J=8.8 Hz),7.06 (1H, d, J=7.7 Hz), 7.19-7.26 (1H, m), 7.31 (1H, , J=7.7 Hz), 7.41(2H, d, J=8.8 Hz), 7.66-7.79 (2H, m), 8.52 (1H, d, J=4.2 Hz), 9.96 (1H,s) negative ESI-MS(m/z): 377 (M−H)⁻

EXAMPLE 252

[1497] The following compound was obtained in substantially the samemanner as in Example 250.

[1498]N-(4-{Formyl[2-(2-pyridinyl)ethyl]amino}phenyl)-2,6-bis(methylthio)nicotinamide

[1499]¹H-NMR(DMSO-d₆): δ 2.51 (6H, s), 2.91 (2H, t, J=7.3 Hz), 4.11 (2H,t, J=7.3 Hz), 7.14-7.32 (5H, m), 7.64-7.76 (3H, m), 7.83 (1H, d, J=8.1Hz), 8.34 (1H, s), 8.46-8.49 (1H, m), 10.42 (1H, s)

EXAMPLE 253

[1500] The following compound was obtained in substantially the samemanner as in Example 92.

[1501]2,6-Bis(methylthio)-N-(4-{[2-(2-pyridinyl)ethyl]amino}phenyl)nicotinamide

[1502]¹H-NMR(DMSO-d₆): δ 2.50 (3H, s), 2.60 (3H, s), 2.99 (2H, t, J=7.3Hz), 3.37 (2H, t, J=7.3 Hz), 5.62 (1H, s), 6.58 (2H, J=8.7 Hz), 7.11(1H, d, J=8.1 Hz), 7.22-7.36 (2H, m), 7.40 (2H, d, J=8.7 Hz), 7.67-7.79(1H, m), 7.94 (1H, d, J=8.0 Hz), 8.50-8.53 (1H, m), 9.94 (1H, s)ESI-MS(m/z): 433(M+Na)⁺, 411(M+H)⁺

EXAMPLE 254

[1503] The following compound was obtained in substantially the samemanner as in Example 91.

[1504]N-(4-{Formyl[2-(2-pyridinyl)ethyl]amino}phenyl)-2-isopropoxy-4-methylbenzamide

[1505]¹H-NMR(DMSO-d₆): δ 1.32 (6H, d, J=6.0 Hz), 2.32 (3H, s), 2.91 (2H,t, J=7.3 Hz), 4.05-4.15 (2H, m), 4.75-4.87 (1H, m), 6.90 (1H, d, J=7.9Hz), 7.05 (1H, s), 7.20-7.33 (4H, m), 7.64-7.76 (4H, m), 8.34 (1H, s),8.46-8.48 (1H, m), 10.17 (1H, s)

EXAMPLE 255

[1506] The following compound was obtained in substantially the samemanner as in Example 92.

[1507]2-Isopropoxy-4-methyl-N-(4-{[2-(2-pyridinyl)ethyl]amino}phenyl)benzamide

[1508]¹H-NMR(DMSO-d₆): δ 1.39 (6H, d, J=6.0 Hz), 2.35 (3H, s), 2.99 (2H,t, J=7.3 Hz), 3.34-3.41 (2H, m), 4.75-4.88 (1H, m), 5.61 (1H, s), 6.60(2H, d, J=8.8 Hz), 6.88 (1H, d, J=7.9 Hz), 7.03 (1H, s), 7.19-7.26 (1H,m), 7.32 (1H, d, J=7.7 Hz), 7.42 (2H, d, J=8.8 Hz), 7.67-7.79 (2H, m),8.52 (1H, d, J=4.3 Hz), 9.84 (1H, s) ESI-MS(m/z):412(M+Na)⁺, 390(M+H)⁺

EXAMPLE 256

[1509] The following compound was obtained in substantially the samemanner as in Example 91.

[1510]4-Chloro-N-(4-{formyl[2-(2-pyridinyl)ethyl]amino}phenyl)-2-isopropoxybenzamide

[1511]¹H-NMR(DMSO-d₆) δ 1.36 (6H, d, J=6.0 Hz), 2.91 (2H, t J=7.3 Hz),3.98-4.15 (2H, m), 4.77-4.89 (1H, m), 7.10-7.31 (6H, m), 7.64-7.76 (4H,m), 8.35 (1H, s), 8.46-8.48 (1H, s), 10.16 (1H, s)

EXAMPLE 257

[1512] The following compound was obtained in substantially the samemanner as in Example 92.

[1513]4-Chloro-2-isopropoxy-N-(4-{[2-(2-pyridinyl)ethyl]amino}phenyl)benzamide

[1514]¹H-NMR(DMSO-d₆): δ 1.36 (6H, d, J=6.0 Hz), 2.99 (2H, t, J=7.4 Hz),3.34-3.41 (2H, m), 4.78-4.90 (1H, m), 5.63 (1H, br.s), 6.60 (2H, d,J=8.8 Hz), 7.09-7.34 (4H, m), 7.42 (2H, d, J=8.8 Hz), 7.67-7.78 (2H, m)8.51-8.53 (1H, m), 9.76 (1H, s) ESI-MS(m/z):432(M+Na)⁺, 410(M+H)⁺

EXAMPLE 258

[1515] To a solution of tert-butyl6-[2-(4-aminophenoxy)ethyl]-2-pyridinylcarbamate (448 mg),2-isopropoxy-4-methylbenzoic acid (291 mg) and 1-hydroxybenzotriazole(250 mg) in N,N-dimethylformamide (30 ml) was added1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (WSC.HCl)(313 mg), followed by triethylamine (0.29 ml) at ambient temperature.The reaction mixture was stirred for 15 hours at the same temperatureand concentrated in vacuo. The residue was dissolved in ethyl acetateand water, and extracted with ethyl acetate. The organic layer waswashed with water and brine, dried over magnesium sulfate, filtered andconcentrated in vacuo. The residue was purified by column chromatographyon silica gel eluting with hexane: ethyl acetate (2:1) to givetert-butyl6-(2-{4-[(2-isopropoxy-4-methylbenzoyl)amino]phenoxy}ethyl)-2-pyridinylcarbamate(495 mg) as a yellow foam.

[1516]¹H-NMR(CDCl₃): δ 1.48(6H, d, J=5.9 Hz), 1.52(9H, s), 2.38(3H, s),3.12(2H, t, J=6.7 Hz), 4.30(2H, t, J=6.7 Hz), 4.73-4.87(1H, m), 6.80(1H,s, J=s Hz), 6.85-6.92(4H, m), 7.54-7.60(3H, m), 7.77(1H, d, J=8.2 Hz),8.17(1H, d, J=8.2 Hz), 10.07(1H, s) ESI-MS(m/z): 506(M+H)⁺

EXAMPLE 259

[1517] To a solution of tert-butyl6-(2-{4-[(2-isopropoxy-4-methylbenzoyl)amino]phenoxy}ethyl)-2-pyridinylcarbamate(485 mg) in dichloromethane (6 ml) was added trifluoroacetic acid (1.48ml). The reaction mixture was stirred for 19 hours at ambienttemperature, quenched with 10% aqueous potassium carbonate solution, andextracted with dichloromethane. The organic layer was washed with brine,dried over magnesium sulfate, filtered and concentrated in vacuo. Theresidue was recrystallized from ethyl acetate-diisopropyl ether to giveN-{4-[2-(6-amino-2-pyridinyl)ethoxy]phenyl}-2-isopropoxy-4-methylbenzamide(327 mg) as a pale yellow solid.

[1518]¹H-NMR(DMSO-d₆): δ 1.37(6H, d, J=5.9 Hz), 2.35(3H, s), 2.92(2H, t,J=6.9 Hz), 4.24(2H, t, J=6.9 Hz), 4.73-4.86(1H, m), 5.83(2H, s),6.29(2H, d, J=7.6 Hz), 6.45(1H, d, J=6.6 Hz), 6.86-6.93(3H, m), 7.03(1H,s), 7.29(1H, dd, J=8.2,7.2 Hz), 7.59(2H, d, J=8.9 Hz), 7.72(1H, d, J=7.9Hz), 9.97(1H, s) ESI-MS(m/z): 406(M+H)⁺

EXAMPLE 260

[1519] The following compound was obtained in substantially the samemanner as in Example 258.

[1520] tert-Butyl(2-{6-[(tert-butoxycarbonyl)amino]-2-pyridinyl)ethyl){4-[(2-isopropoxy-4-methylbenzoyl)amino]phenylcarbamate

[1521]¹H-NMR(CDCl₃): δ 1.41(18H, s), 1.51(6H, d, J=5.9 Hz), 2.39(3H, s),3.04(2H, t, J=5.3 Hz), 3.93(2H, t, J=5.3 Hz), 4.77-4.86(1H, m), 6.82(1H,s), 6.92(1H, d, J=7.9 Hz), 7.08(2H, d, J=7.9 Hz), 7.14(2H, d, J=8.6 Hz),7.58-7.65(3H, m), 8.17(1H, d, J=7.9 Hz), 10.21(1H, s) ESI-MS(m/z):605(M+H)⁺

EXAMPLE 261

[1522] The following compound was obtained in substantially the samemanner as in Example 259.

[1523]N-(4-{[2-(6-Amino-2-pyridinyl)ethyl]amino}phenyl)-2-isopropoxy-4-methylbenzamide

[1524]¹H-NMR(DMSO-d₆): δ 1.38(6H, d, J=5.9 Hz), 2.35(3H, s), 2.73(2H, t,J=7.2 Hz), 3.24-3.31(2H, m), 4.76-4.85(1H, m), 5.56(1H, t, J=5.6 Hz),5.83(2H, s), 6.28(1H, d, J=7.9 Hz), 6.40(1H, d, J=7.2 Hz), 6.59(2H, d,J=8.6 Hz), 6.88(1H, d, J=7.9 Hz), 7.02(1H, s), 7.27(1H, d, J=7.6 Hz),7.40(2H, d, J=8.9 Hz), 7.75(1H, d, J=7.9 Hz), 9.82(1H, s) ESI-MS(m/z):405(M+H)⁺

EXAMPLE 262

[1525] The following compound was obtained in substantially the samemanner as in Example 258.

[1526] tert-Butyl2-{2-[(tert-butoxycarbonyl)amino]-1,3-thiazol-4-yl}ethyl{4-[(2-isopropoxy-4-methylbenzoyl)amino]phenyl}carbamate

[1527]¹H-NMR(CDCl₃): δ 1.49(18H, s), 1.51(6H, d, J=5.9 Hz), 2.39(3H, s),2.94(2H, t, J=7.9 Hz), 3.91(2H, t, J=7.9 Hz), 4.77-4.86(1H, m), 6.80(2H,d, J=9.6 Hz), 6.92(1H, dd, J=7.2,0.6 Hz), 7.13(2H, d, J=8.6 Hz),7.63(2H, d, J=8.6 Hz), 8.17(1H, d, J=7.9 Hz), 10.21(1H, s) ESI-MS(m/z):611(M+H)⁺

EXAMPLE 263

[1528] The following compound was obtained in substantially the samemanner as in Example 259.

[1529]N-(4-{[2-(2-Amino-1,3-thiazol-4-yl)ethyl]amino}phenyl)-2-isopropoxy-4-methylbenzamide

[1530]¹H-NMR(DMSO-d₆): δ 1.39(6H, d, J=5.9 Hz), 2.35(3H, s), 2.66(2H, t,J=7.3 Hz), 3.23(2H, t, J=7.3 Hz), 4.74-4.88(1H, m), 5.52(1H, s),6.21(1H, s), 6.57(2H, s, J=8.9 Hz), 6.85(2H, s), 6.87(1H, dd, J=7.9,0.6Hz), 7.02(1H, s), 7.40(2H, d, J=8.9 Hz), 7.75(1H, d, J=7.9 Hz), 9.82(1H,s) ESI-MS(m/z): 411(M+H)⁺

EXAMPLE 264

[1531] To a solution of tert-butyl4-[2-(4-aminophenoxy)ethyl]-1,3-thiazol-2-ylcarbamate (252 mg),2-isopropoxy-4-methylbenzoic acid (153 mg) and 1-hydroxybenzotriazole(126 mg) in N,N-dimethylformamide (2.5 ml) was added1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (WSC.HCl)(158 mg), followed by triethylamine (91 mg) at ambient temperature. Thereaction mixture was stirred for 19 hours at ambient temperature andconcentrated in vacuo. The residue was dissolved in ethyl acetate andwater, and extracted with ethyl acetate. The organic layer was washedwith water and brine, dried over magnesium sulfate, filtered andconcentrated in vacuo. The residue was purified by column chromatographyon silica gel eluting with hexane: ethyl acetate (4:1→2:1) to givetert-butyl[4-(2-{4-[(2-isopropoxy-4-methylbenzoyl)amino]phenoxy}ethyl)-1,3-thiazol-2-yl]carbamate(0.316 g) as a pale yellow foam.

[1532]¹H-NMR(CDCl₃): δ 1.50(6H, d, J=5.9 Hz), 1.54(9H, s), 2.39(3H, s),3.12(2H, t, J=6.8 Hz), 4.24(2H, t, J=7.0 Hz), 4.81(1H, sept, J=5.9 Hz),6.80-6.93(4H, m), 7.57(2H, d, J=8.9 Hz), 8.17(2H, d, J=8.1 Hz),10.08(1H, s) ESI-MS(m/z): 534(M+Na)⁺

EXAMPLE 265

[1533] To a solution of tert-butyl4-(2-{4-[(2-isopropoxy-4-methylbenzoyl)amino]phenoxy}ethyl)-1,3-thiazol-2-ylcarbamate(312 mg) in dichloromethane (3.1 ml) was added trifluoroacetic acid(0.705 ml). The mixture was stirred for 12 hours, quenched with 10%aqueous potassium carbonate solution and extracted with dichloromethane.The organic layer was washed with brine, dried over magnesium sulfate,filtered and concentrated in vacuo. The residue was recrystallized fromhexane-ethyl acetate to giveN-{4-[2-(2-Amino-1,3-thiazol-4-yl)ethoxy]phenyl}-2-isopropoxy-4-methylbenzamide(0.182 g) as pale brown powder.

[1534]¹H-NMR(CDCl₃): δ 1.51(6H, d, J=6.2 Hz), 2.39(3H, s), 3.02(2H, t,J=6.5 Hz), 4.24(2H, t, J=7.0 Hz), 4.81(1H, sept, J=6.5 Hz), 4.98(2H, brs), 6.27(1H, s), 6.81(1H, s), 6.89-6.92(3H, m), 7.58(2H, d, J=8.9 Hz),8.17(1H, d, J=8.4 Hz), 10.08(1H, s) ESI-MS(m/z): 412(M+H)⁺

[1535] Preparation 154

[1536] To a solution of tert-butyl6-nitro-3,4-dihydro-2(1H)-isoquinolinecarboxylate (495 mg),2-chloro-6-methylnicotinic acid (359 mg) and 1-hydroxybenzotriazole (320mg) in N,N-dimethylformamide (5 ml) was added1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (WSC.HCl)(401 mg), followed by N,N-dimethylaminopyridine (4.86 mg) at ambienttemperature. The reaction mixture was stirred for 12 hours at ambienttemperature and concentrated in vacuo. The residue was dissolved inethyl acetate and water, and extracted with ethyl acetate. The organiclayer was washed with water and brine, dried over magnesium sulfate,filtered and concentrated in vacuo. The residue was purified by columnchromatography on silica gel eluting with hexane: ethyl acetate(6:1→2:1) to give tert-butyl6-{[(2-chloro-6-methyl-3-pyridinyl)carbonyl]amino)-3,4-dihydro-2(1H)-isoquinolinecarboxylate(0.768 g) as a pale yellow foam.

[1537]¹H-NMR(CDCl₃): δ 1.49(9H, s), 2.54(3H, s), 2.83(2H, t, J=5.9 Hz),3.63(2H, t, J=5.9 Hz), 4.53(2H, s), 7.08(1H, d, J=8.4 Hz), 7.16(1H, d,J=7.8 Hz), 7.41-7.70(2H, m), 8.03(1H, d, J=7.6 Hz), 8.63(1H, br s)ESI-MS(m/z): 402(M+H)⁺

[1538] Preparation 155

[1539] To a solution of tert-butyl6-{[(2-chloro-6-methyl-3-pyridinyl)carbonyl]amino}-3,4-dihydro-2(1H)-isoquinolinecarboxylate(1.23 g) in tetrahydrofuran (17 ml) was added 4-methylpiperidine (911mg). The reaction mixture was stirred for 4 hours at 60° C. The mixturewas poured into water and extracted with ethyl acetate. The organiclayer was washed with water and brine, dried over magnesium sulfate,filtered and concentrated in vacuo. The residue was purified by columnchromatography on silica gel eluting with hexane: ethyl acetate (2:1) togive tert-butyl6-({[6-methyl-2-(4-methyl-1-piperidinyl)-3-pyridinyl]carbonyl}amino)-3,4-dihydro-2(1H)-isoquinolinecarboxylate(0.758 g) as a white solid.

[1540]¹H-NMR(CDCl₃): δ 1.03(3H, d, J=6.5 Hz), 1.35-1.50(12H, m),1.84(2H, br d, J=12.7 Hz), 2.52(3H, s), 2.86(2H, t, J=5.4 Hz), 3.00(2H,td, J=12.2, 4.6 Hz), 3.34(2H, d, J=12.7 Hz), 3.65(2H, t, J=5.7 Hz),4.56(2H, s), 7.02(1H, d, J=7.7 Hz), 7.10(1H, d, J=8.1 Hz), 7.20-7.54(1H,m), 7.56-7.89(1H, m), 8.34(1H, d, J=7.8 Hz), 11.76(1H, s) ESI-MS(m/z):465(M+H)⁺

[1541] Preparation 156

[1542] To a solution of tert-butyl6-({[6-methyl-2-(4-methyl-1-piperidinyl)-3-pyridinyl]carbonyl}amino)-3,4-dihydro-2(1H)-isoquinolinecarboxylate(742.9 mg) in dichloromethane (7.4 ml) was added trifluoroacetic acid(0.62 ml). The mixture was stirred for 48 hours, quenched with 10%aqueous potassium carbonate solution, and extracted withdichloromethane. The organic layer was washed with brine, dried overmagnesium sulfate, filtered and concentrated in vacuo. The residue wasrecrystallized from hexane-ethyl acetate to give6-methyl-2-(4-methyl-1-piperidinyl)-N-(1,2,3,4-tetrahydro-6-isoquinolinyl)nicotinamide(0.338 g) as a pale yellow solid.

[1543]¹H-NMR(CDCl₃): δ 1.03(3H, d, J=6.2 Hz), 1.42(2H, td, J=11.1, 2.2Hz), 1.53-1.70(1H, m), 1.86(2H, dd, J=12.4, 2.4 Hz), 2.52(3H, s),3.00(2H, br t, J=11.9 Hz), 3.15(2H, br t, J=5.9 Hz), 3.33(2H, br d,J=19.2 Hz), 3.44(2H, br t, J=5.9 Hz), 4.30(2H, s), 7.03(1H, d, J=7.8Hz), 7.10(1H, d, J=8.4 Hz), 7.39(1H, d, J=7.8 Hz), 7.80(1H, s), 8.33(1H,d, J=7.6 Hz), 11.90(1H, s) ESI-MS(m/z): 365(M+H)⁺

EXAMPLE 266

[1544] To a solution of6-methyl-2-(4-methyl-1-piperidinyl)-N-(1,2,3,4-tetrahydro-6-isoquinolinyl)nicotinamide(200 mg) in tetrahydrofuran (4 ml) was added triethylamine (83 mg) and(1-trityl-1H-1,2,4-triazol-3-yl)methyl methanesulfonate (276 mg). Themixture was stirred at ambient temperature for 17 hours. The reactionmixture was poured into water and extracted with ethyl acetate. Theorganic layer was washed with brine, dried over magnesium sulfate andevaporated in vacuo. The residue was purified by column chromatographyon silica gel eluting with hexane: ethyl acetate (2:1→1:1) to give6-methyl-2-(4-methyl-1-piperidinyl)-N-{2-[(1-trityl-1H-1,2,4-triazol-3-yl)methyl]-1,2,3,4-tetrahydro-6-isoquinolinyl}nicotinamide(196 mg) as a pale yellow foam.

[1545]¹H-NMR(CDCl₃): δ 1.02(3H, d, J=6.2 Hz), 1.34-1.51(2H, m),1.52-1.72(1H, m), 1.84(2H, br d, J=11.3 Hz), 2.51(3H, s), 2.80-3.10(6H,m), 3.35(2H, br d, J=13.0 Hz), 3.68(2H, s), 3.91(2H, s), 6.94(1H, d,J=8.1 Hz), 7.00(1H, d, J=8.1 Hz), 7.09-7.25(6H, m), 7.28-7.43(11H, m),7.55(1H, s), 7.94(1H, s), 8.33(1H, d, J=7.8 Hz), 11.61(1H, s)ESI-MS(m/z): 688(M+H)⁺

EXAMPLE 267

[1546] To a solution of6-methyl-2-(4-methyl-1-piperidinyl)-N-{2-[(1-trityl-1H-1,2,4-triazol-3-yl)methyl]-1,2,3,4-tetrahydro-6-isoquinolinyl}nicotinamide(196 mg) in methanol (2.0 ml) was added 35% hydrochloric acid (0.12 ml).The mixture was stirred at ambient temperature for 12 hours. The mixturewas poured into water and saturated sodium bicarbonate solution andextracted with ethyl acetate. The organic layer was washed with brine,dried over magnesium sulfate and evaporated in vacuo. The residue wasrecrystallized from ethyl acetate-hexane to give6-methyl-2-(4-methyl-1-piperidinyl)-N-[2-(1H-1,2,4-triazol-3-ylmethyl)-1,2,3,4-tetrahydro-6-isoquinolinyl]nicotinamide(92 mg) as white powder.

[1547]¹H-NMR(DMSO-d₆): δ 0.88(3H, d, J=6.2 Hz), 1.12-1.25(2H, m),1.35-1.58(1H, m), 1.62(2H, br d, J=12.4 Hz), 2.39(3H, s), 2.72-2.90(6H,m), 3.57(2H, s), 3.63(2H, br d, J=12.7 Hz), 3.78(2H, s), 6.83(1H, d,J=7.6 Hz), 7.00(1H, d, J=8.1 Hz), 7.39(1H, dd, J=8.1, 1.6 Hz), 7.55(1H,s), 7.75(1H, d, J=7.6 Hz), 8.16(1H, m), 10.46(1H, s) ESI-MS(m/z):446(M+H)⁺

EXAMPLE 268

[1548] To a solution of6-methyl-2-(4-methyl-1-piperidinyl)-N-(1,2,3,4-tetrahydro-6-isoquinolinyl)nicotinamide(128 mg) in dichloromethane (1.3 ml) were added 4-formylbenzonitrile(92.1 mg) and sodium triacetoxyborohydride (223 mg). The mixture wasstirred at ambient temperature for 2.5 hours. The reaction mixture wasquenched with 10% aqueous potassium carbonate solution and extractedwith ethyl acetate. The organic layer was washed with brine, dried overmagnesium sulfate, filtered and concentrated in vacuo. The residue wasrecrystallized from ethyl acetate-hexane to giveN-[2-(4-cyanobenzyl)-1,2,3,4-tetrahydro-6-isoquinolinyl]-6-methyl-2-(4-methyl-1-piperidinyl)nicotinamide(117 mg) as pale yellow powder.

[1549]¹H-NMR(DMSO-d₆): δ 0.89(3H, d, J=6.2 Hz), 1.12-1.25(2H, m),1.48-1.58(1H, m), 1.62(2H, br d, J=12.7 Hz), 2.39(3H, s), 2.67-2.90(6H,m), 3.51(2H, s), 3.63(2H, br d, J=12.7 Hz), 3.74(2H, s), 6.82(1H, d,J=7.6 Hz), 6.98(1H, d, J=8.4 Hz), 7.38(1H, d, J=8.4 Hz), 7.71(3H, d,J=7.8 Hz), 7.74(1H, d, J=7.6 Hz), 7.81(2H, d, J=7.8 Hz), 10.45(1H, s)ESI-MS(m/z): 480(M+H)⁺

[1550] Preparation 157

[1551] The following compound was obtained in substantially the samemanner as in Preparation 155.

[1552] tert-Butyl6-({[2-(dimethylamino)-6-methyl-3-pyridinyl]carbonyl}amino)-3,4-dihydro-2(1H)-isoquinolinecarboxylate

[1553]¹H-NMR(CDCl₃): δ 1.50(9H, s), 2.52(3H, s), 2.84-2.92(8H, m),3.65(2H, br t, J=5.1 Hz), 4.56(2H, s), 6.97(1H, d, J=7.6 Hz), 7.10(1H,d, J=8.4 Hz), 7.20-7.80(2H, m), 8.26(1H, d, J=7.8 Hz), 10.80(1H, s)ESI-MS(m/z): 433(M+Na)⁺

[1554] Preparation 158

[1555] The following compound was obtained in substantially the samemanner as in Preparation 156.

[1556]2-(Dimethylamino)-6-methyl-N-(1,2,3,4-tetrahydro-6-isoquinolinyl)nicotinamide

[1557]¹H-NMR(CDCl₃): δ 2.52(3H, s), 2.79(1H, br s), 2.80-3.10(8H, m),3.21(2H, t, J=5.9 Hz), 4.06(2H, s), 6.96(1H, d, J=7.8 Hz), 7.01(1H, d,J=8.1 Hz), 7.34(1H, d, J=8.4 Hz), 7.54(1H, s), 8.24(1H, d, J=7.6 Hz),10.78(1H, s) ESI-MS(m/z): 311(M+H)⁺

EXAMPLE 269

[1558] The following compound was obtained in substantially the samemanner as in Example 266.

[1559]2-(Dimethylamino)-6-methyl-N-{2-[(1-trityl-1H-1,2,4-triazol-3-yl)methyl]-1,2,3,4-tetrahydro-6-isoquinolinyl}nicotinamide

[1560]¹H-NMR(CDCl₃): δ 2.51(3H, s), 2.75-3.00(10H, m), 3.68(2H, s),3.91(2H, s), 6.94(2H, dd, J=8.1, 3.0 Hz), 7.14-1.24(6H, m),7.25-7.35(9H, m), 7.47(1H, s), 7.54(1H, d, J=6.8 Hz), 7.97(1H, s),8.25(1H, d, J=7.8 Hz), 10.67(1H, s) ESI-MS(m/z): 634(M+H)⁺

EXAMPLE 270

[1561] The following compound was obtained in substantially the samemanner as in Example 267.

[1562]2-(Dimethylamino)-6-methyl-N-[2-(1H-1,2,4-triazol-3-ylmethyl)-1,2,3,4-tetrahydro-6-isoquinolinyl}nicotinamide

[1563]¹H-NMR(CDCl₃): δ 2.50(3H, s), 2.72-2.90(8H, s), 3.55(2H, s),3.60(2H, d, J=12.5 Hz), 3.78(2H, s), 6.92(2H, br d, J=7.3 Hz), 7.02(1H,br s), 7.36(1H, br s), 7.70(1H, br s), 8.00-8.20(2H, m) ESI-MS(m/z):392(M+H)⁺

[1564] Preparation 159

[1565] To a solution of tert-butyl6-amino-3,4-dihydro-2(1H)-isoquinolinecarboxylate (261.6 mg),2-isopropoxy-4-methylbenzoic acid (225 mg) and 1-hydroxybenzotriazole(178 mg) in N,N-dimethylformamide (2 ml) was added1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (WSC.HCl)(222 mg), followed by N,N-dimethylaminopyridine (6.44 mg) at ambienttemperature. The reaction mixture was stirred for 14 hours at ambienttemperature and concentrated in vacuo. The residue was dissolved inethyl acetate and water, and extracted with ethyl acetate. The organiclayer was washed with water and brine, dried over magnesium sulfate,filtered and concentrated in vacuo. The residue was purified by columnchromatography on silica gel eluting with hexane: ethyl acetate (6:1) togive tert-butyl6-[(2-isopropoxy-4-methylbenzoyl)amino]-3,4-dihydro-2(1H)-isoquinolinecarboxylate(0.267 g) as yellow oil.

[1566]¹H-NMR(CDCl₃): δ 1.47-1.52(15H, m), 2.40(3H, s), 2.85(2H, t, J=5.7Hz), 3.64(2H, t, J=5.7 Hz), 4.55(2H, s), 4.82(1H, sept, J=5.9 Hz),6.82(1H, S), 6.92(1H, d, J=7.8 Hz), 7.08(1H, d, J=8.1 Hz), 7.15-7.85(1H,m), 8.17(1H, d, J=7.8 Hz), 10.16(1H, s) ESI-MS(m/z): 447(M+Na)⁺

[1567] Preparation 160

[1568] To a solution of tert-butyl6-[(2-isopropoxy-4-methylbenzoyl)amino]-3,4-dihydro-2(1H)-isoquinolinecarboxylate(260 mg) in dichloromethane (2.6 ml) was added trifluoroacetic acid(0.472 ml). The mixture was stirred for 14 hours, quenched with 10%aqueous potassium carbonate solution, and extracted with ethylacetate—tetrahydrofuran. The organic layer was washed with brine, driedover magnesium sulfate, filtered and concentrated in vacuo. The residuewas purified by column chromatography on silica gel eluting withchloroform: methanol (6:1) to give2-isopropoxy-4-methyl-N-(1,2,3,4-tetrahydro-6-isoquinolinyl)benzamide(0.141 g) as a pale yellow solid.

[1569]¹H-NMR(CDCl₃): δ 1.51(6H, d, J=5.9 Hz), 2.39(3H, s), 3.07(2H, t,J=5.9 Hz), 3.37(2H, t, J=5.9 Hz), 4.22(2H, s), 4.81(1H, sept, J=6.5 Hz),6.81(1H, s), 6.91(1H, d, J=8.4 Hz), 7.05(1H, d, J=8.6 Hz), 7.32(1H, dd,J=8.6, 2.2 Hz), 7.69(1H, s), 8.14(1H, d, J=8.4 Hz), 10.18(1H, s)ESI-MS(m/z): 325(M+H)⁺

EXAMPLE 271

[1570] To a solution of2-isopropoxy-4-methyl-N-(1,2,3,4-tetrahydro-6-isoquinolinyl)benzamide(131.2 mg) in tetrahydrofuran (1.3 ml) was added triethylamine (61.4 mg)and (1-trityl-1H-1,2,4-triazol-3-yl)methyl methanesulfonate (187 mg).The mixture was stirred at ambient temperature for 16 hours. Thereaction mixture was poured into water and extracted with ethyl acetate.The organic layer was washed with brine, dried over magnesium sulfate,filtered and evaporated in vacuo. The residue was purified by columnchromatography on silica gel eluting with hexane: ethyl acetate(1:6→1:8) to give2-isopropoxy-4-methyl-N-{2-[(1-trityl-1H-1,2,4-triazol-3-yl)methyl]-1,2,3,4-tetrahydro-6-isoquinolinyl}benzamide(0.121 g) as a pale yellow foam.

[1571]¹H-NMR(CDCl₃): δ 1.50(6H, d, J=5.9 Hz), 2.39(3H, s), 2.82(2H, t,J=5.7 Hz), 2.91(2H, t, J=5.1 Hz), 3.68(2H, s), 3.91(2H, s), 4.80(1H,sept, J=5.9 Hz), 6.81(1H, s), 6.92(2H, d, J=8.6 Hz), 7.14-7.19(6H, m),7.29-7.55(10H, m), 7.55(1H, s), 7.95(1H, s), 8.17(1H, d, J=8.1 Hz),10.10(1H, s) ESI-MS(m/z): 670(M+Na)⁺

EXAMPLE 272

[1572] To a solution of2-isopropoxy-4-methyl-N-{2-[(1-trityl-1H-1,2,4-triazol-3-yl)methyl]-1,2,3,4-tetrahydro-6-isoquinolinyl}benzamide(114.3 mg) in methanol (2.0 ml) was added 35% hydrochloric acid (27.4μl). The mixture was stirred at ambient temperature for 18 hours. Themixture was poured into water and saturated sodium bicarbonate solution,and extracted with ethyl acetate. The organic layer was washed withbrine, dried over magnesium sulfate, filtered and evaporated in vacuo.The residue was recrystallized from ethyl acetate-hexane to give2-isopropoxy-4-methyl-N-[2-(1H-1,2,4-triazol-3-ylmethyl)-1,2,3,4-tetrahydro-6-isoquinolinyl]benzamide(0.056 g) as pale yellow powder.

[1573]¹H-NMR(DMSO-d₆): δ 1.51(6H, d, J=6.2 Hz), 2.40(3H, s), 2.87(2H, t,J=5.1 Hz), 2.98(2H, t, J=5.1 Hz), 3.74(2H, s), 3.96(2H, s), 4.81(1H,sept, J=6.2 Hz), 6.82(1H, s), 6.92(1H, d, J=7.8 Hz), 6.97(1H, d, J=8.3Hz), 7.27(1H, d, J=8.3 Hz), 7.65(1H, s), 8.00(1H, s), 8.17(1H, d, J=8.4Hz), 10.15(1H, s) ESI-MS(m/z): 406(M+H)⁺

[1574] Preparation 161

[1575] The following compound was obtained in substantially the samemanner as in Preparation 159.

[1576] tert-Butyl6-{[2-(dimethylamino)benzoyl]amino}-3,4-dihydro-2(1H)-isoquinolinecarboxylate

[1577]¹H-NMR(CDCl₃): δ 1.50(9H, s), 2.83-2.89(8H, m), 3.65(2H, t, J=5.4Hz), 4.55(2H, s), 7.09(1H, d, J=8.4 Hz), 7.24-7.80(5H, m), 8.26(1H, dd,J=7.8, 1.4 Hz), 12.11(1H, s) ESI-MS(m/z): 418(M+Na)⁺

[1578] Preparation 162

[1579] The following compound was obtained in substantially the samemanner as in Preparation 160.

[1580] 2-(Dimethylamino)-N-(1,2,3,4-tetrahydro-6-isoquinolinyl)benzamide

[1581]¹H-NMR(CDCl₃): δ 2.83(6H, s), 3.13(2H, t, J=5.9 Hz), 3.43(2H, t,J=5.9 Hz), 4.28(2H, s), 7.08(1H, d, J=8.4 Hz), 7.24-7.27(1H, m),7.31(1H, d, J=7.0 Hz), 7.39(1H, dd, J=8.6, 2.4 Hz), 7.46-7.52(1H, m),7.69(1H, s), 8.23(1H, dd, J=7.8, 1.4 Hz), 12.30(1H, s) ESI-MS(m/z):296(M+H)⁺

EXAMPLE 273

[1582] The following compound was obtained in substantially the samemanner as in Example 271.

[1583]2-(Dimethylamino)-N-{2-[(1-trityl-1H-1,2,4-triazol-3-yl)methyl]-1,2,3,4-tetrahydro-6-isoquinolinyl}benzamide

[1584]¹H-NMR(CDCl₃): δ 2.80-2.89(8H, m), 2.92(2H, t, J=5.1 Hz), 3.69(2H,s), 3.91(2H, s), 6.93(1H, d, J=8.1 Hz), 7.14-7.44(18H, m), 7.47(1H, dd,J=2.7, 1.1 Hz), 7.50(1H, d, J=1.6 Hz), 7.95(1H, s), 8.29(1H, dt, J=7.8,1.4 Hz), 12.00(1H, s) ESI-MS(m/z): 619(M+H)⁺

EXAMPLE 274

[1585] The following compound was obtained in substantially the samemanner as in Example 272.

[1586]2-(Dimethylamino)-N-[2-(1H-1,2,4-triazol-3-ylmethyl)-1,2,3,4-tetrahydro-6-isoquinolinyl]benzamide

[1587]¹H-NMR(CDCl₃): δ 2.79-2.85(8H, m), 2.97(2H, t, J=5.4 Hz), 3.72(2H,s), 3.93(2H, s), 6.98(1H, d, J=8.4 Hz), 7.23-7.40(3H, m), 7.45-7.52(1H,m), 7.61(1H, s), 8.26(1H, dd, J=7.6, 1.1 Hz), 12.11(1H, s) ESI-MS(m/z):377(M+H)⁺

EXAMPLE 275

[1588] To a solution of tert-butyl4-aminophenyl[2-(1H-pyrazol-1-yl)ethyl]carbamate (363 mg),2-(4-methylphenyl)-1-cyclohexene-1-carboxylic acid (286 mg) and1-hydroxybenzotriazole hydrate (221 mg) in N,N-dimethylformamide (5 ml)was added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride(276 mg) at ambient temperature. The reaction mixture was stirred for 21hours at the same temperature and concentrated in vacuo. The residue wasdissolved in ethyl acetate and water, and extracted with ethyl acetate.The organic layer was washed with water and brine, dried over magnesiumsulfate, filtered and concentrated in vacuo. The residue was purified bycolumn chromatography on silica gel eluting with hexane: ethyl acetate(1:1) to give tert-butyl[4-({[2-(4-methylphenyl)-1-cyclohexen-1-yl]carbonyl}amino)phenyl][2-(1H-pyrazol-1-yl)ethyl]carbamate(297 mg) as a yellow foam.

[1589]¹H-NMR(CDCl₃): δ 1.37(9H, s), 1.76(4H, br s), 2.32(3H, s),2.41(2H, br s), 2.50(2H, br s), 3.94(2H, t, J=6.2 Hz), 4.29(2H, t, J=6.1Hz), 6.20(1H, t, J=2.0 Hz), 6.61(1H, s), 6.75(2H, br s), 6.89(2H, d,J=8.6 Hz), 7.15(4H, br s), 7.34(1H, d, J=2.0 Hz), 7.45(1H, d, J=1.6 Hz)ESI-MS(m/z): 523(M+Na)⁺

EXAMPLE 276

[1590] To a solution of tert-butyl4-({[2-(4-methylphenyl)-1-cyclohexen-1-yl]carbonyl}amino)phenyl[2-(1H-pyrazol-1-yl)ethyl]carbamate(292 mg) in dichloromethane (10 ml) was added trifluoroacetic acid(0.674 ml). The reaction mixture was stirred for 20 hours at ambienttemperature, quenched with 10% aqueous potassium carbonate solution andextracted with dichloromethane. The organic layer was washed with brine,dried over magnesium sulfate, filtered and concentrated in vacuo. Theresidue was recrystallized from ethyl acetate-diisopropyl ether to give2-(4-methylphenyl)-N-(4-{[2-(1H-pyrazol-1-yl)ethyl]amino}phenyl)-1-cyclohexene-1-carboxamide(200 mg) as a white solid.

[1591]¹H-NMR(DMSO-d₆): δ 1.69(4H, br s), 2.21(3H, s), 2.35(4H, br s),3.37(2H, t, J=6.4 Hz), 4.22(2H, t, J=6.4 Hz), 6.20(1H, t, J=2.0 Hz),6.47(2H, d, J=8.9 Hz), 7.04(1H, d, J=7.9 Hz), 7.08(1H, d, J=8.9 Hz),7.17(1H, d, J=7.9 Hz), 7.44(1H, d, J=1.3 Hz), 7.69(1H, d, J=2.0 Hz),9.11(1H, s) ESI-MS(m/z): 401(M+H)⁺

EXAMPLE 277

[1592] To a solution of 4′-(trifluoromethyl)[1,1′-biphenyl]-2-carboxylicacid (384 mg) in toluene (5 ml) were added thionyl chloride (342 mg) andN,N-dimethylformamide (1 drop) and the mixture was stirred at 50° C. foran hour. The mixture was evaporated in vacuo and the residue wasdissolved in tetrahydrofuran (2 ml). The acid chloride intetrahydrofuran was added to a solution of tert-butyl4-aminophenyl[2-(1H-pyrazol-1-yl)ethyl]carbamate (363 mg) andtriethylamine (0.25 ml) in tetrahydrofuran (8 ml) at ambient temperatureand the mixture was stirred at the same temperature for an hour. Themixture was poured into water and extracted with ethyl acetate. Theorganic layer was washed with brine, dried over magnesium sulfate andevaporated in vacuo. The residue was purified by column chromatographyon silica gel eluting with hexane: ethyl acetate (1:1) to givetert-butyl2-(1H-pyrazol-1-yl)ethyl[4-({[4′-(trifluoromethyl)-1,1′-biphenyl-2-yl]carbonyl}amino)phenyl]carbamate(660 mg) as a yellow foam.

[1593]¹H-NMR(CDCl₃): δ 1.38(9H, s), 3.97(2H, t, J=6.1 Hz), 4.31(2H, t,J=6.1 Hz), 6.21(1H, t, J=2.0 Hz), 6.81(2H, br s), 7.01(1H, s), 7.08(2H,d, J=8.6 Hz), 7.35(1H, d, J=2.0 Hz), 7.41-7.59(6H, m), 7.67(2H, d, J=7.9Hz), 7.78(1H, dd, J=7.6, 1.3 Hz) ESI-MS(m/z): 573(M+Na)⁺

EXAMPLE 278

[1594] To a solution of tert-butyl2-(1H-pyrazol-1-yl)ethyl[4-({[4′-(trifluoromethyl)-1,1′-biphenyl-2-yl]carbonyl}amino)phenyl]carbamate(660 mg) in dichloromethane (10 ml) was added trifluoroacetic acid(0.674 ml). The reaction mixture was stirred for 20 hours at ambienttemperature, quenched with 10% aqueous potassium carbonate solution andextracted with dichloromethane. The organic layer was washed with brine,dried over magnesium sulfate, filtered and concentrated in vacuo. Theresidue was recrystallized from ethyl acetate-diisopropyl ether to giveN-(4-{[2-(1H-pyrazol-1-yl)ethyl]amino}phenyl)-4′-(trifluoromethyl)-1,1′-biphenyl-2-carboxamide(464 mg) as a white solid.

[1595]¹H-NMR(DMSO-d₆): δ 3.42(2H, t, J=6.2 Hz), 4.26(2H, t, J=6.2 Hz),6.22(1H, t, J=2.0 Hz), 6.59(2H, d, J=8.6 Hz), 7.25(2H, d, J=8.9 Hz),7.45-7.64(7H, m), 7.71-7.26(3H, m), 10.01(1H, s) ESI-MS(m/z): 451(M+H)⁺

EXAMPLE 279

[1596] The following compound was obtained in substantially the samemanner as in Example 277.

[1597] tert-Butyl4-{[(4′-methyl-1,1′-biphenyl-2-yl)carbonyl]amino}phenyl[2-(1H-pyrazol-1-yl)ethyl]carbamate

[1598]¹H-NMR(CDCl₃): δ 1.39(9H, s), 2.40(3H, s), 3.97(2H, t, J=6.1 Hz),4.31(2H, t, J=6.1 Hz), 6.22(1H, t, J=2.0 Hz), 6.82(2H, br s), 6.91(1H,s), 7.04(2H, d, J=8.9 Hz), 7.25(2H, d, J=8.9 Hz), 7.33-7.55(7H, m),7.87(1H, dd, J=8.2, 1.3 Hz) ESI-MS(m/z): 519(M+Na)⁺

EXAMPLE 280

[1599] The following compound was obtained in substantially the samemanner as in Example 278.

[1600]4′-Methyl-N-(4-{[2-(1H-pyrazol-1-yl)ethyl]amino}phenyl)-1,1′-biphenyl-2-carboxamide

[1601]¹H-NMR(DMSO-d₆): δ 2.29(3H, s), 3.38(2H, q, J=6.2 Hz), 4.23(2H, t,J=6.4 Hz), 5.53(1H, t, J=6.1 Hz), 6.21(1H, t, J=2.0 Hz), 6.48(2H, d,J=8.9 Hz), 7.17(2H, d, J=7.9 Hz), 7.23(2H, d, J=8.9 Hz), 7.34(2H, d,J=7.9 Hz), 7.39-7.54(5H, m), 7.71(1H, d, J=2.0 Hz), 9.81(1H, s)ESI-MS(m/z): 419(M+Na)⁺

[1602] Preparation 163

[1603] A solution of N-(4-nitrophenyl)-N-[2-(1H-pyrazol-1-yl)ethyl]amine(300 mg) in methanol (8 ml) was hydrogenated over 10% palladium oncarbon (60 mg, 50% wet) at ambient temperature under atmosphericpressure of hydrogen for an hour. The reaction mixture was filtered withpad of Celite, and the filtrate was concentrated in vacuo to giveN-[2-(1H-pyrazol-1-yl)ethyl]-1,4-benzenediamine (261 mg) as a yellowoil. The product was used at the next step without purification.

[1604]¹H-NMR(CDCl₃): δ 3.41(2H, br s), 3.51-3.55(3H, m), 4.29-4.33(2H,m), 6.24(1H, t, J=2.0 Hz), 6.49(2H, d, J=8.6 Hz), 6.60(2H, d, J=8.6 Hz),7.35(1H, d, J=2.3 Hz), 7.54(1H, d, J=1.6 Hz) ESI-MS(m/z): 525(M+Na)⁺

EXAMPLE 281

[1605] To a solution of N-[2-(1H-pyrazol-1-yl)ethyl]-1,4-benzenediamine(251 mg), 4′-ethyl-1,1′-biphenyl-2-carboxylic acid (309 mg) and1-hydroxybenzotriazole hydrate (228 mg) in N,N-dimethylformamide (8 ml)was added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride(285 mg) at ambient temperature. The reaction mixture was stirred for 4hours at the same temperature and concentrated in vacuo. The residue wasdissolved in ethyl acetate and water, and extracted with ethyl acetate.The organic layer was washed with water and brine, dried over magnesiumsulfate, filtered and concentrated in vacuo. The residue wasrecrystallized from ethyl acetate-diisopropyl ether to give4′-ethyl-N-(4-{[2-(1H-pyrazol-1-yl)ethyl]amino}phenyl)-1,1′-biphenyl-2-carboxamide(282 mg) as a white solid.

[1606]¹H-NMR(DMSO-d₆): δ 1.17(3H, t, J=7.6 Hz), 2.60(2H, q, J=7.6 Hz),3.39(2H, q, J=6.3 Hz), 4.23(2H, t, J=6.3 Hz), 5.53(1H, t, J=6.1 Hz),6.21(1H, t, J=2.0 Hz), 6.48(2H, d, J=8.9 Hz), 7.19-7.22(4H, m),7.34-7.54(7H, m), 7.71(1H, d, J=2.0 Hz), 9.80(1H, s) ESI-MS(m/z):433(M+Na)⁺

EXAMPLE 282

[1607] To a solution of 2-isopropoxy-4-methylbenzoic acid (266 mg) intoluene (5 ml) were added thionyl chloride (245 mg) andN,N-dimethylformamide (1 drop), and the mixture was stirred at 50° C.for 30 minutes. The mixture was evaporated in vacuo and the residue wasdissolved in tetrahydrofuran (4 ml). The acid chloride intetrahydrofuran was added to a solution of tert-butyl4-aminophenyl[2-(1H-pyrazol-1-yl)ethyl]carbamate (413 mg) andtriethylamine (152 mg) in tetrahydrofuran (10 ml) at ambienttemperature, and the mixture was stirred at the same temperature for 13hours. The mixture was poured into water and extracted with ethylacetate. The organic layer was washed with brine, dried over magnesiumsulfate, and concentrated in vacuo. The residue was purified by columnchromatography on silica gel eluting with hexane:ethyl acetate (1:1) togive tert-butyl4-[(2-isopropoxy-4-methylbenzoyl)amino]phenyl[2-(1H-pyrazol-1-yl)ethyl]carbamate(516 mg) as a colorless oil.

[1608]¹H-NMR(CDCl₃): δ 1.40(9H, s), 1.51(6H, d, J=6.0 Hz), 2.40(3H, s),4.03(2H, t, J=6.1 Hz), 4.36(2H, t, J=6.1 Hz), 4.82(1H, sept, J=6.0 Hz),6.24(1H, t, J=2.0 Hz), 6.82(1H, s), 6.85-7.03(3H, m), 7.39(1H, d, J=2.0Hz), 7.49(1H, d, J=2.0 Hz), 7.59(2H, d, J=8.2 Hz), 8.17(1H, d, J=7.9Hz), 10.20(1H, s) (+)ESI-MS(m/z): 501(M+Na)⁺

EXAMPLE 283

[1609] The following compound was obtained in substantially the samemanner as in Example 179.

[1610]2-Isopropoxy-4-methyl-N-(4-{[2-(1H-pyrazol-1-yl)ethyl]amino}phenyl)benzamide

[1611]¹H-NMR(CDCl₃): δ 1.49(6H, d, J=5.9 Hz), 2.38(3H, s), 3.60(2H, t,J=5.6 Hz), 3.94(1H, brs), 4.34(2H, t, J=5.6 Hz), 4.80(1H, sep, J=5.9Hz), 6.25(1H, t, J=2.0 Hz), 6.60(2H, d, J=8.9 Hz), 6.80(1H, s), 6.90(1H,d, J=7.9 Hz), 7.35(1H, d, J=2.0 Hz), 7.49(2H, d, J=8.9 Hz), 7.55(1H, d,J=1.6 Hz), 8.17(1H, d, J=8.2 Hz), 9.99(1H, s) (+)ESI-MS(m/z): 401(M+Na)⁺

EXAMPLE 284

[1612] To a solution of 2-isopropoxy-4-methylbenzoic acid (443 mg) intoluene (3.5 ml) were added thionyl chloride (0.331 ml) andN,N-dimethylformamide (8.4 mg) and the mixture was stirred at 80° C. foran hour. The mixture was evaporated in vacuo and the residue wasdissolved in tetrahydrofuran (1.3 ml). The acid chloride solution wasadded to a solution ofN-[2-(6-amino-3,4-dihydroisoquinolin-2(1H)-yl)ethyl]acetamide (409.6 mg)and triethylamine (0.367 ml) in tetrahydrofuran (2.0 ml) at ambienttemperature and the mixture was stirred at the same temperature for 2hours. The mixture was poured into water and extracted with ethylacetate. The extract was washed with brine, dried over magnesium sulfateand evaporated in vacuo. The residue was purified by columnchromatography on silica gel eluting with chloroform: methanol (95:5) togiveN-{2-[2-(acetylamino)ethyl]-1,2,3,4-tetrahydro-6-isoquinolinyl}-2-isopropoxy-4-methylbenzamide(0.399 g) as pale yellow powder.

[1613]¹H-NMR(CDCl₃): δ 1.51(6H, d, J=5.9 Hz), 1.97(3H, s), 2.40(3H, s),2.67(2H, t, J=5.9 Hz), 2.77(2H, t, J=5.9 Hz), 2.94(2H, t, J=5.9 Hz),3.45(2H, q, J=5.9 Hz), 3.63(2H, s), 4.82(1H, sept, J=5.9 Hz), 6.17(1H,br s), 6.82(1H, s), 6.92(1H, d, J=7.8 Hz), 7.01(1H, d, J=8.1 Hz),7.28(1H, dd, J=8.1, 2.4 Hz), 7.66(1H, d, J=1.9 Hz), 8.17(1H, d, J=7.8Hz), 10.14(1H, s) ESI-MS (m/z): 410(M+H)⁺

EXAMPLE 285

[1614] To a solution ofN-[2-(6-amino-3,4-dihydroisoquinolin-2(1H)-yl)ethyl]acetamide (331.6mg), 2-(dimethylamino)benzoic acid (280 mg) and 1-hydroxybenzotriazole(261 mg) in N,N-dimethylformamide (3.3 ml) was added1-[3-(dimethylamino)propyl]-3 -ethylcarbodiimide hydrochloride (WSC.HCl)(327 mg), followed by triethylamine (0.296 ml) at ambient temperature.The reaction mixture was stirred for an hour at ambient temperature andconcentrated in vacuo. The residue was dissolved in ethyl acetate andwater, and extracted with ethyl acetate. The organic layer was washedwith water and brine, dried over magnesium sulfate, filtered andconcentrated in vacuo. The residue was purified by column chromatographyon silica gel eluting with chloroform: methanol (95:5) to giveN-{2-[2-(acetylamino)ethyl]-1,2,3,4-tetrahydro-6-isoquinolinyl}-2-(dimethylamino)benzamide(0.505 g) as a pale yellow foam.

[1615]¹H-NMR(CDCl₃): δ 1.97(3H, s), 2.66(2H, t, J=5.9 Hz), 2.76(2H, t,J=5.7 Hz), 2.83(6H, s), 2.94(2H, t, J=5.7 Hz), 3.44(2H, q, J=5.9 Hz),3.62(2H, s), 6.17(1H, br s), 7.02(1H, d, J=8.1 Hz), 7.23-7.35(3H, m),7.48(1H, ddd, J=7.8, 5.1, 1.6 Hz), 7.61(1H, d, J=1.9 Hz), 8.25(1H, dd,J=7.6, 1.1 Hz), 12.08(1H, s) ESI-MS(m/z): 381(M+H)⁺

EXAMPLE 286

[1616] The following compound was obtained in substantially the samemanner as in Example 182.

[1617] tert-Butyl4-({[2-(4-methylphenyl)-3-pyridinyl]carbonyl}amino)phenyl[2-(1H-pyrazol-1-yl)ethyl]carbamate

[1618]¹H-NMR(CDCl₃): δ 1.39(9H, s), 2.40(3H, s), 3.98(2H, t, J=6.1 Hz),4.32(2H, t, J=6.1 Hz), 6.23(1H, t, J=2.0 Hz), 6.83(2H, d, J=7.2 Hz),7.09(2H, d, J=8.6 Hz), 7.14(1H, s), 7.27(2H, d, J=7.6 Hz), 7.34-7.39(2H,m), 7.46(1H, d, J=1.6 Hz), 7.58(2H, d, J=7.9 Hz), 8.15(1H, dd, J=7.9,1.7 Hz), 8.76(1H, dd, J=4.8, 1.8 Hz) ESI-MS(m/z): 520(M+Na)⁺

EXAMPLE 287

[1619] The following compound was obtained in substantially the samemanner as in Example 183.

[1620]2-(4-Methylphenyl)-N-(4-{[2-(1H-pyrazol-1-yl)ethyl]amino}phenyl)nicotinamide

[1621]¹H-NMR(DMSO-d₆): δ 2.31(3H, s), 3.40(2H, q, J=6.3 Hz), 4.24(2H, t,J=6.3 Hz), 5.60(1H, t, J=6.0 Hz), 6.22(1H, t, J=2.0 Hz), 6.52(2H, d,J=8.9 Hz), 7.21(2H, d, J=8.0 Hz), 7.26(2H, d, J=8.9 Hz), 7.41-7.46(2H,m), 7.62(2H, d, J=8.2 Hz), 7.72(1H, d, J=1.7 Hz), 7.90(1H, dd, J=7.6,1.7 Hz), 8.71(1H, dd, J=4.8, 1.8 Hz), 10.02(1H, s) ESI-MS(m/z):398(M+H)⁺

EXAMPLE 288

[1622] The following compound was obtained in substantially the samemanner as in Example 182.

[1623] tert-Butyl4-({[2-(4-ethylphenyl)-3-pyridinyl]carbonyl}amino)phenyl[2-(1H-pyrazol-1-yl)ethyl]carbamate

[1624]¹H-NMR(CDCl₃): δ 1.26(3H, t, J=7.6 Hz), 1.39(9H, s), 2.71(2H, q,J=7.6 Hz), 3.97(2H, t, J=6.3 Hz), 4.32(2H, t, J=6.3 Hz), 6.22(1H, t,J=2.0 Hz), 6.81(2H, d, J=7.3 Hz), 7.05(2H, d, J=8.9 Hz), 7.11(1H, s),7.31(2H, d, J=8.2 Hz), 7.35-7.40(2H, m), 7.46(1H, d, J=1.6 Hz), 7.61(2H,d, J=8.2 Hz), 8.18(1H, dd, J=7.9, 1.0 Hz), 8.77(1H, dd, J=4.7, 1.8 Hz)ESI-MS(m/z): 534(M+Na)⁺

EXAMPLE 289

[1625] The following compound was obtained in substantially the samemanner as in Example 183.

[1626]2-(4-Ethylphenyl)-N-(4-{[2-(1H-pyrazol-1-yl)ethyl]amino}phenyl)nicotinamide

[1627]¹H-NMR(DMSO-d₆): δ 1.18(3H, t, J=7.6 Hz), 2.62(2H, q, J=7.6 Hz),3.40(2H, q, J=0.3 Hz), 4.24(2H, t, J=6.3 Hz), 5.60(1H, t, J=6.0 Hz),6.22(1H, t, J=2.0 Hz), 6.52(2H, d, J=8.9 Hz), 7.22-7.27(4H, m),7.41-7.46(2H, m), 7.64(2H, d, J=8.2 Hz), 7.72(1H, d, J=2.3 Hz), 7.90(1H,dd, J=7.6, 1.7 Hz), 8.72(1H, dd, J=4.6, 1.7 Hz), 10.38(1H, s)ESI-MS(m/z): 412(M+H)⁺

EXAMPLE 290

[1628] To a solution of 2-(4-methylphenyl)-1-cyclohexene-1-carboxylicacid (291 mg) in toluene (2.9 ml) were added thionyl chloride (0.195 ml)and N,N-dimethylformamide (1 drop) and the mixture was stirred at 80° C.for an hour. The mixture was evaporated in vacuo, and the residue wasdissolved in tetrahydrofuran (1.0 ml). The acid chloride was added to asolution of tert-butyl 5-amino-2-pyridinyl[2-(1H-pyrazol-1-yl)ethyl]carbamate (314 mg) and triethylamine (0.22 ml) in tetrahydrofuran(2.14 ml) at ambient temperature and the mixture was stirred at the sametemperature for 16 hours. The mixture was poured into water andextracted with ethyl acetate. The organic layer was washed with brine,dried over magnesium sulfate and evaporated in vacuo. The residue waspurified by column chromatography on silica gel eluting withhexane:ethyl acetate (4:1→3:1→1:1) to give tert-butyl5-({[2-(4-methylphenyl)-1-cyclohexen-1-yl]carbonyl}amino)-2-pyridinyl[2-(1H-pyrazol-1-yl)ethyl]carbamate(311 mg) as a pale yellow foam.

[1629]¹H-NMR(CDCl₃): δ 1.42(9H, s), 1.77(4H, m), 2.35(3H, s), 2.43(2H,br s), 2.53(2H, br s), 4.25(2H, t, J=5.4 Hz), 4.36(2H, t, J=5.4 Hz),6.17(1H, t, J=2.2 Hz), 6.61(1H, br s), 7.17(4H, s), 7.30-7.31(2H, m),7.42(1H, d, J=1.9 Hz), 7.55(1H, dd, J=8.4, 2.4 Hz), 7.73(1H, d, J=2.7Hz) ESI-MS(m/z): 524(M+Na)⁺

EXAMPLE 291

[1630] To a solution of tert-butyl5-({[2-(4-methylphenyl)-1-cyclohexen-1-yl]carbonyl}amino)-2-pyridinyl[2-(1H-pyrazol-1-yl)ethyl]carbamate(304 mg) in dichloromethane (3 ml) was added trifluoroacetic acid (0.7ml). The reaction mixture was stirred for 18 hours, quenched with 10%aqueous potassium carbonate solution, and extracted withdichloromethane. The organic layer was washed with brine, dried overmagnesium sulfate, filtered and concentrated in vacuo. The residue wasrecrystallized from ethyl acetate-hexane to give2-(4-methylphenyl)-N-(6-{[2-(1H-pyrazol-1-yl)ethyl]amino)-3-pyridinyl)-1-cyclohexene-1-carboxamide(182 mg) as pale yellow powder.

[1631]¹H-NMR(CDCl₃): δ 1.75-1.78(4H, m), 2.34(3H, s), 2.41(2H, br s),2.51(2H, br s), 3.72(2H, q, J=5.7 Hz), 4.31(2H, t, J=5.7 Hz), 4.62(1H,br t, J=5.9 Hz), 6.21(1H, d, J=2.4 Hz), 6.24(1H, d, J=7.6 Hz), 6.41(1H,br s), 7.13-7.20(4H, m), 7.31-7.37(2H, m), 7.40(1H, br d, J=2.4 Hz),7.52(1H, d, J=1.4 Hz) ESI-MS(m/z): 402(M+H)⁺

EXAMPLE 292

[1632] The following compound was obtained in substantially the samemanner as in Example 290.

[1633] tert-Butyl{5-[(2-isopropoxy-4-methylbenzoyl)amino]-2-pyridinyl}[2-(1H-pyrazol-1-yl)ethyl]carbamate

[1634]¹H-NMR(CDCl₃): δ 1.46(9H, s), 1.53(6H, d, J=6.5 Hz), 2.41(3H, s),4.33(2H, t, J=5.1 Hz), 4.44(2H, t, J=5.7 Hz), 4.85(1H, sept, J=6.2 Hz),6.20(1H, t, J=1.9 Hz), 6.84(1H, s), 6.93(1H, d, J=8.9 Hz), 7.37(1H, dd,J=2.4, 0.5 Hz), 7.45-7.49(2H, m), 8.17(1H, d, J=7.8 Hz), 8.27(1H, dd,J=8.9, 2.7 Hz), 8.44(1H, d, J=2.4 Hz), 10.28(1H, s) ESI-MS(m/z):502(M+Na)⁺

EXAMPLE 293

[1635] The following compound was obtained in substantially the samemanner as in Example 291.

[1636]2-Isopropoxy-4-methyl-N-(6-{[2-(1H-pyrazol-1-yl)ethyl]amino}-3-pyridinyl)benzamide

[1637]¹H-NMR(CDCl₃): δ 1.50(6H, d, J=5.9 Hz), 2.39(3H, s), 3.81(2H, q,J=5.7 Hz), 4.38(2H, t, J=5.1 Hz), 4.70(1H, br t, J=5.9 Hz), 4.81(1H,sept, J=5.9 Hz), 6.24(1H, t, J=2.2 Hz), 6.41(1H, d, J=8.9 Hz), 6.81(1H,s), 6.91(1H, d, J=7.8 Hz), 7.36(1H, d, J=1.6 Hz), 7.55(1H, d, J=1.1 Hz),8.07(1H, dd, J=8.9, 2.7 Hz), 8.14(2H, m), 10.01(1H, s) ESI-MS(m/z):380(M+H)⁺

EXAMPLE 294

[1638] A mixture of 2-(4-methylphenyl)-1-cyclohexene-1-carboxylic acid(325 mg), 4-[2-(1H-pyrazol-1-yl)ethoxy]phenylamine (321 mg),1-hydroxybenzotriazole hydrate (242 mg) and1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide (245 mg) inN,N-dimethylformamide (20 ml) was stirred at ambient temperature for 15hours. The reaction mixture was poured into a mixture of ethyl acetateand water, and the organic layer was washed with brine and dried overmagnesium sulfate. The solvent was evaporated in vacuo and the residuewas chromatographed on silica gel eluting with ethyl acetate: n-hexane(6:4 v/v). The eluting fraction was concentrated in vacuo and theprecipitate was collected by filtration to give2-(4-methylphenyl)-N-{4-[2-(1H-pyrazol-1-yl)ethoxy]phenyl}-1-cyclohexene-1-carboxamide(398 mg).

[1639]¹H-NMR(DMSO-d₆): δ 1.70(4H, br.s), 2.30(3H, s), 2.34(4H, br.s),4.23(2H, t, J=5.3 Hz), 4.44(2H, t, J=5.3 Hz), 6.22-6.23(1H, m), 6.74(2H,d, J=9.3 Hz), 7.03(1H, d, J=8.1 Hz), 7.18(1H, d, J=8.1 Hz), 7.25(2H, d,J=9.3 Hz), 7.44(1H, d, J=1.4 Hz), 7.75(1H, d, J=2.0 Hz), 9.37(1H, s)ESI-MS(m/z): 424(M+Na)⁺, 402(M+H)⁺

EXAMPLE 295

[1640] The following compound was obtained in substantially the samemanner as in Example 294.

[1641]N-{4-[2-(1H-Pyrazol-1-yl)ethoxy]phenyl}-2-[4-(trifluoromethyl)phenyl]-1-cyclohexene-1-carboxamide

[1642]¹H-NMR(DMSO-d₆): δ 1.73(4H, br.s), 2.39(4H, br.s), 4.23(2H, t,J=5.2 Hz), 4.44(2H, t, J=5.2 Hz), 6.21-6.23(1H, m), 6.74 (2H, d, J=9.9Hz), 7.21(2H, d, J=9.0 Hz),7.44(1H, d, J=1.7 Hz), 7.47(2H, d, J=8.3 Hz),7.62 (2H, d, J=8.3 Hz), 7.74 (1H, d, J=2.2 Hz), 9.50 (1H, s)ESI-MS(m/z): 478(M+Na)⁺, 456(M+H)⁺

EXAMPLE 296

[1643] The following compound was obtained in substantially the samemanner as in Example 294.

[1644]2-[4-(Dimethylamino)phenyl]-N-{4-[2-(1H-pyrazol-1-yl)ethoxy]phenyl}-1-cyclohexene-1-carboxamide

[1645]¹H-NMR(DMSO-d₆): δ 1.68 (4H, br.s), 2.32 (4H, br.s), 2.81 (6H, s),4.23 (2H, t, J=5.3 Hz), 4.44 (2H, t, J=5.3 Hz), 6.22-6.23 (1H, m), 6.65(2H, d, J=8.8 Hz), 6.74 (2H, d, J=9.0 Hz), 7.14 (2H, d, J=8.8 Hz), 7.23(2H, d, J=9.0 Hz), 7.44 (1H, d, J=1.5 Hz), 7.74 (1H, d, J=2.2 Hz), 9.30(1H, s) ESI-MS(m/z): 453(M+Na)⁺, 431(M+H)⁺

EXAMPLE 297

[1646] The following compound was obtained in substantially the samemanner as in Example 294.

[1647]2-(4-Methylphenyl)-N-{6-[2-(1H-pyrazol-1-yl)ethoxy]-3-pyridinyl}-1-cyclohexene-1-carboxamide

[1648]¹H-NMR(DMSO-d₆): δ 1.71 (4H, br.s), 2.21 (3H, s), 2.36 (4H, br.s),4.42-4.52 (4H, m), 6.21-6.23 (1H, m), 6.65 (1H, d, J=8.4 Hz), 7.05 (2H,d, J=8.0 Hz), 7.18 (2H, d, J=8.0 Hz),7.43 (1H, d, J=1.4 Hz), 7.64 (1H,dd, J=2.7, 8.8 Hz), 7.72 (1H, d, J=2.1 Hz), 8.09 (1H, d, J=2.7 Hz), 9.53(1H, s) ESI-MS(m/z): 425(M+Na)⁺, 403(M+H)⁺

EXAMPLE 298

[1649] The following compound was obtained in substantially the samemanner as in Example 294.

[1650]N-{6-[2-(1H-Pyrazol-1-yl)ethoxy]-3-pyridinyl)-2-[4-(trifluoromethyl)phenyl]-1-cyclohexene-1-carboxamide

[1651]¹H-NMR(DMSO-d₆): δ 1.74 (4H, br.s), 2.40 (2H, br.s), 4.04-4.54(4H, m), 6.20-6.22 (1H, m), 6.65 (1H, d, J=9.0 Hz), 7.42-7.76 (7H, m),8.06 (1H, d, J=2.5 Hz), 9.67 (1H, s) ESI-MS(m/z): 479(M+Na)⁺, 457(M+H)⁺

EXAMPLE 299

[1652] The following compound was obtained in substantially the samemanner as in Example 294.

[1653]2-(4-Methylphenyl)-N-{4-[2-(1H-1,2,4-triazol-1-yl)ethoxy]phenyl}-1-cyclohexene-1-carboxamide

[1654]¹H-NMR(DMSO-d₆): δ 1.70(4H, br.s), 2.20(3H, s), 2.34(4H, br.s),4.25(2H, t, J=5.0 Hz), 4.53(2H, t, J=5.0 Hz), 6.74(2H, d, J=9.0 Hz),6.84(2H, d, J=9.0 Hz), 7.03(1H, d, J=8.0 Hz), 7.17(2H, d, J=8.0 Hz),7.98(1H, s), 8.54(1H, s), 9.37(1H, s)

EXAMPLE 300

[1655] The following compound was obtained in substantially the samemanner as in Example 294.

[1656]N-{4-[2-(1H-1,2,4-Triazol-1-yl)ethoxy]phenyl}-2-[4-(trifluoromethyl)phenyl]-1-cyclohexene-1-carboxamide

[1657]¹H-NMR(DMSO-d₆): δ 1.73(4H, br.s), 2.39(4H, br.s), 4.25(2H, t,J=5.0 Hz), 4.53(2H, t, J=5.0 Hz), 6.75(2H, d, J=9.0 Hz), 7.22(2H, d,J=9.0 Hz), 7.48(2H, d, J=8.3 Hz), 7.62(2H, d, J=8.3 Hz), 7.93(1H, s),8.54(1H, s), 9.51(1H, s)

EXAMPLE 301

[1658] The following compound was obtained in substantially the samemanner as in Example 294.

[1659]2-(4-Methylphenyl)-N-(4-{[2-(1H-1,2,4-triazol-1-yl)ethyl]amino}phenyl)-1-cyclohexene-1-carboxamide

[1660]¹H-NMR(DMSO-d₆): δ 1.69(4H, br.s), 2.22(3H, s), 2.33(4H, br.s),3.24-3.43(2H, m), 4.27(2H, t, J=6.0 Hz), 5.52(1H, t, J=6.0 Hz), 6.41(2H,d, J=8.8 Hz), 7.02-7.08(4H, m), 7.18(1H, d, J=8.1 Hz), 7.97(1H, s),8.44(1H, s), 9.10(1H, s) ESI-MS(m/z): 424(M+Na)⁺, 402(M+H)⁺

EXAMPLE 302

[1661] The following compound was obtained in substantially the samemanner as in Example 294.

[1662]N-(4-{[2-(1H-1,2,4-Triazol-1-yl)ethyl]amino}phenyl)-2-[4-(trifluoromethyl)phenyl]-1-cyclohexene-1-carboxamide

[1663]¹H-NMR(DMSO-d₆): δ 1.72(4H, br.s), 2.38(4H, br.s), 3.35-3.41(2H,m), 4.28(2H, t, J=6.1 Hz), 5.52(1H, t, J=6.1 Hz), 6.42(2H, d, J=8.8 Hz),7.01(2H, d, J=8.8 Hz), 7.48(1H, d, J=8.2 Hz), 7.63(2H, d, J=8.2 Hz),7.97(1H, s), 8.44(1H, s), 9.24(1H, s) ESI-MS(m/z): 477(M+Na)⁺, 456(M+H)⁺

EXAMPLE 303

[1664] The following compound was obtained in substantially the samemanner as in Example 294.

[1665]N-{4-[3-(1H-1,2,4-Triazol-1-yl)propyl]phenyl}-2-[4-(trifluoromethyl)phenyl]-1-cyclohexene-1-carboxamide

[1666]¹H-NMR(DMSO-d₆): δ 1.74 (4H, br.s), 1.87-2.16 (2H, m), 2.40 (4H,br.s), 2.04-2.48 (2H, m), 4.14 (2H, t, J=7.0 Hz), 7.02 (2H, d, J=8.4Hz), 7.26 (2H, d, J=8.4 Hz), 7.49 (2H, d, J=8.3 Hz), 7.62 (2H, d, J=8.3Hz), 7.96 (1H, s), 8.50 (1H, s), 9.61 (1H, s) ESI-MS(m/z): 477(M+Na)⁺,455(M+H)⁺

EXAMPLE 304

[1667] A mixture of 4′-(dimethylamino)-1,1′-biphenyl-2-carboxylic acid(242 mg), 4-[2-(1H-1,2,4-triazol-1-yl)ethoxy]aniline (215 mg),1-hydroxybenzotriazole (142 mg) and1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide (163 mg) inN,N-dimethylformamide (20 ml) was stirred at ambient temperature for 15hours. The reaction mixture was poured into a mixture of ethyl acetateand water, and the organic layer was washed with brine and dried overmagnesium sulfate. The solvent was evaporated in vacuo and the residuewas chromatographed on silica gel eluting with ethyl acetate:methanol(94:6 v/v). The eluted fractions were concentrated in vacuo and theprecipitate was collected by filtration to give4′-(dimethylamino)-N-{4-[2-(1H-1,2,4-triazol-1-yl)ethoxy]phenyl}-1,1′-biphenyl-2-carboxamide(300 mg).

[1668]¹H-NMR(DMSO-d₆): δ 2.88(6H, s), 4.29(2H, t, J=4.9 Hz), 4.55(2H, t,J=4.9 Hz), 6.70(2H, d, J=8.8 Hz), 6.83(2H, d, J=8.9 Hz), 7.29(2H, d,J=8.8 Hz), 7.36-7.53(6H, m), 7.99(1H, s), 8.56(1H,s), 10.06(1H,s)ESI-MS(m/z): 450(M+Na)⁺, 428(M+H)⁺

EXAMPLE 305

[1669] The following compound was obtained in substantially the samemanner as in Example 304.

[1670]N-(4-{[2-(1H-1,2,4-Triazol-1-yl)ethyl]amino}phenyl)-4′-(trifluoromethyl)-1,1′-biphenyl-2-carboxamide

[1671]¹H-NMR(DMSO-d₆): δ 3.38-3.47(2H, m), 4.30(2H, t, J=6.1 Hz),5.61(1H, t, J=6.1 Hz), 6.49(2H, d, J=8.8 Hz), 7.22(2H, d, J=8.8 Hz),7.46-7.65(6H, m), 7.76(2H, d, J=8.4 Hz), 7.98(1H, s), 8.46(1H, s),9.54(1H, s) ESI-MS (m/z): 474 (M+Na)⁺, 452 (M+H)⁺

EXAMPLE 306

[1672] The following compound was obtained in substantially the samemanner as in Example 304.

[1673]4′-Methyl-N-(4-{[2-(1H-1,2,4-triazol-1-yl)ethyl]amino}phenyl)-1,1′-biphenyl-2-carboxamide

[1674]¹H-NMR(DMSO-d₆): δ 2.29(3H, s), 3.38-3.47(2H, m), 4.30(2H, t,J=6.1 Hz), 5.61(1H, t, J=6.1 Hz), 6.49(2H, d, J=8.8 Hz), 7.15-7.56(10H,m), 7.98(1H, s), 8.46(1H, s), 9.84(1H, s) ESI-MS(m/z): 420(M+Na)⁺,398(M+H)⁺

EXAMPLE 307

[1675] The following compound was obtained in substantially the samemanner as in Example 304.

[1676]5-Methyl-N-(4-{[2-(1H-1,2,4-triazol-1-yl)ethyl]amino}phenyl)-4′-(trifluoromethyl)-1,1′-biphenyl-2-carboxamide

[1677]¹H-NMR(DMSO-d₆): δ 2.41(3H, s), 3.38-3.47(2H, m), 4.30(2H, t,J=6.1 Hz), 5.61(1H, t, J=6.0 Hz), 6.49(2H, d, J=8.8 Hz), 7.21(2H, d,J=8.8 Hz), 7.33(1H, d, J=7.6 Hz), 7.35(1H, s), 7.49(1H, d, J=7.6 Hz),7.61(2H, d, J=8.3 Hz), 7.75(2H, d, J=8.3 Hz), 7.98(1H, s), 8.45(1H, s),9.87(1H, s) ESI-MS(m/z): 488(M+Na)⁺, 466(M+H)⁺

EXAMPLE 308

[1678] The following compound was obtained in substantially the samemanner as in Example 304.

[1679]4′,6-Dimethyl-N-{4-[2-(1H-1,2,4-triazol-1-yl)ethoxy]phenyl}-1,1′-biphenyl-2-carboxamide

[1680]¹H-NMR(DMSO-d₆): δ 2.08(3H, s), 2.78(3H, s), 4.27(2H, t, J=5.0Hz), 4.54(2H, t, J=5.0 Hz), 6.77(2H, d, J=9.0 Hz), 7.14(3H, s),7.29-7.42(6H, m), 7.98(1H, s), 8.55(1H, s), 9.87(1H, s) ESI-MS(m/z):435(M+Na)⁺, 413(M+H)⁺

EXAMPLE 309

[1681] The following compound was obtained in substantially the samemanner as in Example 304.

[1682]4′,5-Dimethyl-N-{4-[2-(1H-1,2,4-triazol-1-yl)ethoxy]phenyl}-1,1′-biphenyl-2-carboxamide

[1683]¹H-NMR(DMSO-d₆): δ 2.28(3H, s), 2.38(3H,s), 4.29(2H, t, J=5.0 Hz),4.55(2H, t, J=5.0 Hz), 6.82(2H, d, J=9.0 Hz), 7.15(2H, d, J=8.0 Hz),7.24-7.33(5H, m), 7.41(2H, d, J=8.8 Hz), 7.99(1H, s), 8.56(1H, s),9.99(1H, s) ESI-MS (m/z): 435 (M+Na)⁺, 413 (M+H)⁺

EXAMPLE 310

[1684] The following compound was obtained in substantially the samemanner as in Example 294.

[1685]N-{4-[2-(1H-Pyrazol-1-yl)ethoxy]phenyl}-4′-(trifluoromethyl)-1,1′-biphenyl-2-carboxamide

[1686]¹H-NMR(DMSO-d₆): δ 4.30(2H, t, J=5.2 Hz), 4.46(2H, t, J=5.2 Hz),6.23-6.25(1H, m), 6.83(2H, d, J=9.0 Hz), 7.39-7.64(9H, m), 7.73-7.77(3H,m), 10.22(1H, s)

EXAMPLE 311

[1687] The following compound was obtained in substantially the samemanner as in Example 294.

[1688]4′-(Dimethylamino)-N-{4-[2-(1H-pyrazol-1-yl)ethoxy]phenyl}-1,1′-biphenyl-2-carboxamide

[1689]¹H-NMR(DMSO-d₆): δ 2.87(6H, s), 4.27(2H, t, J=5.3 Hz), 4.46(2H, t,J=5.3 Hz), 6.23-6.25(1H, m), 6.70(2H, d, J=8.8 Hz), 6.83(2H, d, J=9.0Hz), 7.86(2H, d, J=8.7 Hz), 7.31-7.53(7H, m), 7.70(1H, d, J=2.0 Hz),10.06(1H, s) ESI-MS(m/z): 449(M+Na)⁺, 427(M+H)⁺

EXAMPLE 312

[1690] The following compound was obtained in substantially the samemanner as in Example 294.

[1691]N-{6-[2-(1H-Pyrazol-1-yl)ethoxy]-3-pyridinyl}-4′-(trifluoromethyl)-1,1′-biphenyl-2-carboxamide

[1692]¹H-NMR(DMSO-d₆): δ 4.44-4.59(4H, m), 6.22-6.24(1H, m), 6.75(1H, dJ=9.0 Hz), 7.44(1H, d, J=1.5 Hz), 7.51-7.82(10H, m), 8.28(1H, d, J=2.4Hz),10.39(1H, S) ESI-MS(m/z): 475(M+Na)⁺, 453(M+H)⁺

EXAMPLE 313

[1693] The following compound was obtained in substantially the samemanner as in Example 294.

[1694]4′,5-Dimethyl-N-{6-[2-(1H-pyrazol-1-yl)ethoxy]-3-pyridinyl}-1,1′-biphenyl-2-carboxamide

[1695]¹H-NMR(DMSO-d₆): δ 2.29(3H, s), 2.40(3H, s), 4.43-4.58(4H, m),6.22-6.24(1H, m), 6.74(1H, d, J=8.9 Hz), 7.17(2H, d, J=8.0 Hz),7.26-7.33(4H, m), 7.43-7.47(2H, m), 7.73-7.82(2H, m), 8.27(1H, d, J=2.5Hz), 10.16(1H, s) ESI-MS(m/z): 435(M+Na)⁺, 413(M+H)⁺

EXAMPLE 314

[1696] The following compound was obtained in substantially the samemanner as in Example 294.

[1697]4′,5-Dimethyl-N-{4-[2-(1H-pyrazol-1-yl)ethoxy]phenyl}-1,1′-biphenyl-2-carboxamide

[1698]¹H-NMR(DMSO-d₆): δ 2.28(3H, s), 2.39(3H, s), 4.27(2H, d, J=5.3Hz), 4.46(2H, d, J=5.3 Hz), 6.23-6.25(1H, m), 6.81(2H, d, J=8.1 Hz),7.23-7.46(8H, m), 7.76(1H, d, J=2.1 Hz), 9.99(1H, s) ESI-MS(m/z):434(M+Na)⁺, 412(M+H)⁺

EXAMPLE 315

[1699] The following compound was obtained in substantially the samemanner as in Example 294.

[1700]4′-Methoxy-5-methyl-N-{4-[2-(1H-pyrazol-1-yl)ethoxy]phenyl}-1,1′-biphenyl-2-carboxamide

[1701]¹H-NMR(DMSO-d₆): δ 2.39(3H, s), 3.73(3H, s), 4.27(2H, t, J=5.3Hz), 4.46(2H, t, J=5.3 Hz), 6.23-6.25(1H, m), 6.81(2H, d, J=9.0 Hz),6.92(2H, d, J=7.1 Hz), 7.21-7.24(2H, m), 7.32-7.46(6H, m), 7.76(1H, d,J=2.2 Hz), 9.97(1H, s) ESI-MS (m/z): 450 (M+Na)⁺, 428 (M+H)⁺

EXAMPLE 316

[1702] The following compound was obtained in substantially the samemanner as in Example 294.

[1703]4′-Chloro-5-methyl-N-{4-[2-(1H-pyrazol-1-yl)ethoxy]phenyl}-1,1′-biphenyl-2-carboxamide

[1704]¹H-NMR(DMSO-d₆): δ 2.40(3H, s), 4.27(2H, t, J=5.3 Hz), 4.46(2H, t,J=5.3 Hz), 6.23-6.25(1H, m), 6.82(2H, d, J=9.0 Hz), 7.29(2H, d, J=8.4Hz), 7.38-7.48(8H, m), 7.76(1H, d, J=2.2 Hz), 10.05(1H, s) ESI-MS(m/z):454(M+Na)⁺, 432(M+H)⁺

EXAMPLE 317

[1705] The following compound was obtained in substantially the samemanner as in Example 294.

[1706]4′-(Dimethylamino)-5-methyl-N-{4-[2-(1H-pyrazol-1-yl)ethoxy]phenyl}-1,1′-biphenyl-2-carboxamide

[1707]¹H-NMR(DMSO-d₆): δ 2.37(3H, s), 2.88(6H, s), 4.27(2H, t, J=5.2Hz), 4.46(2H, t, J=5.2 Hz), 6.23-6.25(1H, m), 6.69(2H, d, J=8.7 Hz),6.82(2H, d, J=9.0 Hz), 7.14-7.46(8H, m), 7.76(1H, d, J=2.0 Hz), 9.95(1H,s) ESI-MS(m/z): 463(M+Na)⁺, 441(M+H)⁺

EXAMPLE 318

[1708] The following compound was obtained in substantially the samemanner as in Example 304.

[1709]N-{4-[3-(1H-1,2,4-Triazol-1-yl)propyl]phenyl}-4′-(trifluoromethyl)-1,1′-biphenyl-2-carboxamide

[1710]¹H-NMR(DMSO-d₆): δ 1.99-2.12(2H, m), 2.37-2.49(2H, m), 4.16(2H, t,J=7.0 Hz), 7.11(2H, d, J=8.8 Hz), 7.45(2H, d, J=8.4 Hz), 7.49-7.66(6H,m), 7.76(2H, d, J=8.3 Hz), 7.97(1H, s), 8.52(1H, s), 10.32(1H,s)ESI-MS(m/z): 473(M+Na)⁺, 451(M+H)⁺

EXAMPLE 319

[1711] The following compound was obtained in substantially the samemanner as in Example 304.

[1712]4′-(Dimethylamino)-N-{4-[3-(1H-1,2,4-triazol-1-yl)propyl]phenyl}-1,1′-biphenyl-2-carboxamide

[1713]¹H-NMR(DMSO-d₆): δ 1.99-2.18(2H, m), 2.40-2.50(2H, m), 2.88(6H,s), 4.16(2H, t, J=6.9 Hz), 6.70(2H, d, J=8.7 Hz), 7.10(2H, d, J=8.3 Hz),7.29(2H, d, J=8.7 Hz), 7.32-7.51(6H, m), 7.97(1H, s), 8.50(1H, s),10.16(1H,s) ESI-MS(m/z): 448(M+Na)⁺, 425(M+H)⁺

[1714] Preparation 164

[1715] The following compound was obtained in substantially the samemanner as in Preparation 96.

[1716] 1-[2-(4-Nitrophenoxy)ethyl]-1H-pyrrole

[1717]¹H-NMR(DMSO-d₆): δ 4.27-4.46(4H, m), 6.00-6.01(2H, m),6.83-6.85(2H, m), 7.09-7.17(2H, m), 8.15-8.23(2H, m)

[1718] Preparation 165

[1719] The following compound was obtained in substantially the samemanner as in Preparation 97.

[1720] 4-[2-(1H-Pyrrol-1-yl)ethoxy]aniline

[1721]¹H-NMR(DMSO-d₆): δ 3.97-4.07(2H, m), 4.14-4.19(2H, m), 4.62(2H,s), 5.91-5.99(2H, m), 6.45-6.52(2H, m), 6.56-6.68(2H, m), 6.77-6.81(2H,m)

EXAMPLE 320

[1722] The following compound was obtained in substantially the samemanner as in Example 304.

[1723]N-{4-[2-(1H-Pyrrol-1-yl)ethoxy]phenyl}-2-[4-(trifluoromethyl)phenyl]-1-cyclohexene-1-carboxamide

[1724]¹H-NMR(DMSO-d₆): δ 1.74(4H, br.s), 2.39(4H, br.s), 4.01-4.22(4H,m), 5.96-5.98(2H, m), 6.73-6.80(4H, m), 7.22(2H, d, J=9.0 Hz), 7.48(2H,d, J=8.1 Hz), 7.62(2H, d, J=8.1 Hz), 9.49(1H, s) ESI-MS(m/z):477(M+Na)⁺, 455(M+H)⁺

EXAMPLE 321

[1725] The following compound was obtained in substantially the samemanner as in Example 304.

[1726]N-{4-[2-(1H-Pyrrol-1-yl)ethoxy]phenyl}-4′-(trifluoromethyl)-1,1′-biphenyl-2-carboxamide

[1727]¹H-NMR(DMSO-d₆): δ 4.16-4.24(4H, m), 5.98-6.00(2H, m),6.80-6.96(3H, m), 7.42(2H, d, J=9.0 Hz), 7.48-7.65(5H, m), 7.75(2H, d,J=8.3 Hz), 10.21(1H, s) ESI-MS(m/z): 473(M+Na)⁺, 451(M+H)⁺

[1728] Preparation 166

[1729] A solution of chloroacetylchoride (357 mg) in tetrahydrofuran (5ml) was dropwise added to a mixture ofN-(2,3-dihydro-1H-indol-5-yl)-4′-(trifluoromethyl)-1,1′-biphenyl-2-carboxamide(1.15 g) and triethylamine (670 mg) in tetrahydrofuran (30 ml) at 5-20°C. under stirring and the resultant mixture was stirred at ambienttemperature for 6 hours. The reaction mixture was poured into a mixtureof ethyl acetate and water, and the organic layer was washed with brineand dried over magnesium sulfate. The solvent was evaporated in vacuoand the residue was chromatographed on silica gel eluting with ethylacetate and n-hexane (6:4). The fraction was concentrated in vacuo andthe precipitate was collected by filtration to giveN-[1-(chloroacetyl)-2,3-dihydro-1H-indol-5-yl]-4′-(trifluoromethyl)-1,1′-biphenyl-2-carboxamide(1.09 g).

[1730]¹H-NMR(DMSO-d₆): δ 3.13(2H, t, J=8.3 Hz), 4.11(2H, t, J=8.3 Hz),4.51(2H, s), 7.27(1H, dd, J=1.8, 8.6 Hz), 7.50-7.65(7H, m), 7.76(2H, d,J=8.4 Hz), 7.93(1H, d, J=8.6 Hz), 10.33(1H, s)

EXAMPLE 322

[1731] A mixture of imidazole (136 mg) and potassium tert-butoxide (225mg) in N,N-dimethylformamide (10 ml) was stirred at ambient temperaturefor 30 minutes.N-[1-(chloroacetyl)-2,3-dihydro-1H-indol-5-yl]-4′-(trifluoromethyl)-1,1′-biphenyl-2-carboxamide(460 mg) was added to an above mixture and the resultant mixture wasstirred at 65-70° C. for 6 hours. The reaction mixture was poured into amixture of ethyl acetate and water, and the organic layer was washedwith brine and dried over magnesium sulfate. The solvent wasconcentrated in vacuo and the precipitate was collected by filtration togiveN-[1-(1H-imidazol-1-ylacetyl)-2,3-dihydro-1H-indol-5-yl]-4′-(trifluoromethyl)-1,1′-biphenyl-2-carboxamide(340 mg).

[1732]¹H-NMR(DMSO-d₆): δ 3.17(2H, t, J=8.3 Hz), 4.15(2H, t, J=8.3 Hz),5.09(2H, s), 6.89(1H, s), 7.11(1H, s), 7.22(1H, dd, J=1.6, 8.7 Hz),7.49-7.65(8H, m), 7.76(2H, d, J=8.3 Hz), 7.88(1H, d, J=8.7 Hz),10.32(1H, s) ESI-MS(m/z): 513(M+Na)⁺, 491(M+H)⁺

EXAMPLE 323

[1733] A mixture ofN-[1-(chloroacetyl)-2,3-dihydro-1H-indol-5-yl]-4′-(trifluoromethyl)-1,1′-biphenyl-2-carboxamide(460 mg) and 1,2,4-triazole sodium salt (128 mg) inN,N-dimethylformamide (10 ml) was stirred at 65-70° C. for 4.5 hours.The reaction mixture was poured into a mixture of ethyl acetate andwater, and the organic layer was washed with brine and dried overmagnesium sulfate. The solvent was evaporated in vacuo and the residuewas chromatographed on silica gel eluting with ethyl acetate: methanol(95:5-90:10 v/v). The eluted fractions were concentrated in vacuo andthe precipitate was collected by filtration to giveN-[1-(1H-1,2,4-triazol-1-ylacetyl)-2,3-dihydro-1H-indol-5-yl]-4′-(trifluoromethyl)-1,1′-biphenyl-2-carboxamide(370 mg).

[1734]¹H-NMR(DMSO-d₆): δ 3.18(2H, t, J=8.3 Hz), 4.19(2H, t, J=8.3 Hz),5.37(2H, s), 7.22-7.25(1H, m), 7.51-7.64(7H, m), 7.77(2H, d, J=8.3 Hz),7.86(1H, d, J=8.7 Hz), 8.00(1H, s), 8.50(1H, s), 10.33(1H, s) negativeESI-MS(m/z): 490(M−H)⁻

EXAMPLE 324

[1735] The following compound was obtained in substantially the samemanner as in Example 186.

[1736]2-Isopropoxy-4-methyl-N-[2-(2-pyridinylacetyl)-2,3-dihydro-1H-isoindol-5-yl]benzamide

[1737]¹H-NMR(DMSO-d₆): δ 1.37(6H, t, J=6.0 Hz), 2.36(3H, s), 3.4-3.8(6H,m), 4.81(1H, septet, J=6.0 Hz.), 6.8-7.8(8H, m), 8.51(1H, d, J=4.5 Hz),10.03(1H, s) ESI-MS(m/z): 452(M+Na)⁺, 430(M+H)⁺

[1738] Preparation 167

[1739] To a solution of ethyl2-methyl-6-oxo-1,6-dihydro-5-pyrimidinecarboxylate (9.109 g) anddiisopropylethylamine (7.75 g) in 1,2-dichloroethane (200 ml) was addeddropwise trifluoromethanesulfonic anhydride (15.5 g) at 5° C. and themixture was stirred at ambient temperature for 20 hours. The mixture waspoured into iced water (100 ml) and the separated organic layer waswashed with water and brine, dried over magnesium sulfate and dried invacuo. The residue was purified by flash chromatography on silica geleluting with ethyl acetate to give crude ethyl2-methyl-4-{[(trifluoromethyl)sulfonyl]oxy}-5-pyrimidinecarboxylate(14.69 g) as a dark-brown oil.

[1740]¹H-NMR(DMSO-d₆): δ 1.26(3H, t, J=7.1 Hz), 2.35(3H, s), 4.21(2H, q,J=7.1 Hz), 8.44(1H, s) ESI-MS(m/z): 337(M+H)⁺

[1741] Preparation 168

[1742] To a solution of ethyl2-methyl-4-{[(trifluoromethyl)sulfonyl]oxy}-5-pyrimidinecarboxylate(14.67 g) in acetonitrile (70 ml) was added 4-methylpiperidine (13.9 g)and the mixture was refluxed for 16 hours. The mixture was evaporated invacuo and the residue was purified by column chromatography on silicagel eluting with ethyl acetate to give ethyl2-methyl-4-(4-methyl-1-piperidinyl)-5-pyrimidinecarboxylate (10.23 g) asa yellow oil.

[1743]¹H-NMR(DMSO-d₆): δ 0.92(3H, d, J=6.1 Hz), 1.0-1.3(3H, m), 1.32(3H,t, J=7.2 Hz), 1.6-1.8(2H, m), 2.41(3H, s), 2.85-3.05(2H, m),3.9-4.05(2H, m), 4.26(2H, q, J=7.2 Hz), 8.42(1H, s) ESI-MS(m/z):286(M+Na)⁺, 264(M+H)⁺

[1744] Preparation 169

[1745] To a solution of ethyl2-methyl-4-(4-methyl-1-piperidinyl)-5-pyrimidinecarboxylate (10.20 g) inethanol (50 ml) was added 5N aqueous sodium hydroxide solution (15.5 ml)and the mixture was refluxed for 5 hours. The mixture was cooled to 5°C., adjusted to pH 7 by addition of 6N hydrochloric acid and evaporatedin vacuo to remove ethanol. The residue was adjusted to pH 5 by additionof 6N hydrochloric acid and extracted with ethyl acetate. The separatedorganic layer was washed with brine, dried over magnesium sulfate anddried in vacuo. The residue was triturated with diisopropyl ether andcollected by filtration to give2-methyl-4-(4-methyl-1-piperidinyl)-5-pyrimidinecarboxylic acid (4.74 g)as a white crystal.

[1746]¹H-NMR(DMSO-d₆): δ 0.91(3H, d, J=6.0 Hz), 1.0-1.3(2H, m),1.55-1.7(3H, m), 2.39(3H, s), 2.9-3.1(2H, m), 4.0-4.2(2H, m), 8.39(1H,s) ESI-MS(m/z): 258(M+Na)⁺, 236(M+H)⁺

EXAMPLE 325

[1747] To a solution of 4-aminophenyl[2-(2-pyridinyl)ethyl]formamide(724 mg), 2-methyl-4-(4-methyl-1-piperidinyl)-5-pyrimidinecarboxylicacid (706 mg) and benzotriazol-1-yl-oxytripyrrolidinophosphoniumhexafluorophosphate (PyBOP) (1.87 g) in N,N-dimethylformamide (30 ml)was added diisopropylethylamine (776 mg) at ambient temperature and themixture was stirred at the same temperature for 20 hours. The mixturewas poured into a mixture of ethyl acetate, water and 6N hydrochloricacid. The separated organic layer was washed with water and brine, driedover magnesium sulfate and evaporated in vacuo. The residue was purifiedby column chromatography on silica gel eluting with ethyl acetate togiveN-(4-{formyl[2-(2-pyridinyl)ethyl]amino}phenyl)-2-methyl-4-(4-methyl-1-piperidinyl)-5-pyrimidinecarboxamide(926 mg) as a pale brown powder.

[1748]¹H-NMR(DMSO-d₆): δ 0.89(3H, t, J=5.9 Hz), 1.0-1.25(2H, m),1.55-1.8(3H, m), 2.42(3H, s), 2.8-3.1(4H, m), 3.9-4.2(4H, m),7.1-7.3(4H, m), 7.6-7.75(3H, m), 8.23(1H, s), 8.34(1H, s), 8.45-8.5(1H,m), 10.55(1H, s) negative ESI-MS(m/z): 457(M−H)⁻

EXAMPLE 326

[1749] To a suspension ofN-(4-{formyl[2-(2-pyridinyl)ethyl]amino}phenyl)-2-methyl-4-(4-methyl-1-piperidinyl)-5-pyrimidinecarboxamide(910 mg) in methanol (10 ml) was added concentrated hydrochloric acid(0.83 ml) at ambient temperature and the resultant solution was stirredat the same temperature for 20 hours. The solution was poured into amixture of ethyl acetate and water and adjusted to pH 9 by addition of50% potassium carbonate aqueous solution. The separated organic layerwas washed with water and brine, dried over magnesium sulfate andevaporated in vacuo. The residue was purified by column chromatographyon silica gel eluting with ethyl acetate to give2-methyl-4-(4-methyl-1-piperidinyl)-N-(4-{[2-(2-pyridinyl)ethyl]amino}phenyl)-5-pyrimidinecarboxamide(436 mg) as a pale brown powder.

[1750]¹H-NMR(DMSO-d₆): δ 0.88(3H, d, J=6.0 Hz), 1.0-1.3(2H, m),1.5-1.7(3H, m), 2.41(3H, s), 2.8-3.05(4H, m), 3.36(2H, t, J=7.0 Hz),4.05-4.25(2H, m), 5.85(1H, br), 6.57(2H, d, J=8.9 Hz), 7.2-7.3(1H, m),7.31(1H, d, J=7.9 Hz), 7.38(2H, d, J=8.9 Hz), 7.65-7.75(1H, m), 8.17(1H,s), 8.5-8.55(1H, m), 10.07(1H, s) negative ESI-MS(m/z): 429(M−H)⁻

[1751] Preparation 170

[1752] The following compound was obtained in substantially the samemanner as in Preparation 168.

[1753] Ethyl4-(4-methyl-1-piperidinyl)-2-(trifluoromethyl)-5-pyrimidinecarboxylate

[1754]¹H-NMR(DMSO-d6): δ 0.90(3H, t, J=6.1 Hz), 1.1-1.4(2H, m), 1.31(3H,t, J=7.1 Hz), 1.6-1.9(3H, m), 3.0-3.2(2H, m), 3.9-4.1(2H, m), 4.32(2H,q, J=7.1 Hz), 8.64(1H, s) ESI-MS(m/z): 340(M+Na)⁺, 318(M+H)⁺

[1755] Preparation 171

[1756] The following compound was obtained in substantially the samemanner as in Preparation 169.

[1757]4-(4-Methyl-1-piperidinyl)-2-(trifluoromethyl)-5-pyrimidinecarboxylicacid

[1758]¹H-NMR(DMSO-d₆): δ 0.92(3H, d, J=6.1 Hz), 1.05-1.3(2H, m),1.6-1.8(3H, m), 2.95-3.2(2H, m), 3.95-4.15(2H, m), 8.62(1H, s),13.65(1H, brs) negative ESI-MS(m/z): 288(M−H)⁻

EXAMPLE 327

[1759] The following compound was obtained in substantially the samemanner as in Example 325.

[1760]N-(4-{Formyl[2-(2-pyridinyl)ethyl]amino}phenyl)-4-(4-methyl-1-piperidinyl)-2-(trifluoromethyl)-5-pyrimidinecarboxamide

[1761]¹H-NMR(DMSO-d₆): δ 0.90(3H, d, J=6.0 Hz), 1.0-1.3(2H, m),1.5-1.8(3H, m), 2.85-2.95(2H, m), 4.05-4.3(4H, m), 7.15-7.4(4H, m),7.65-7.75(3H, m), 8.36(1H, s), 8.45-8.5(1H, m), 8.50(1H, s), 10.78(1H,s) ESI-MS(m/z): 535(M+Na)⁺, 513(M+H)⁺

EXAMPLE 328

[1762] The following compound was obtained in substantially the samemanner as in Example 326.

[1763]4-(4-Methyl-1-piperidinyl)-N-(4-{[2-(2-pyridinyl)ethyl]amino}phenyl)-2-(trifluoromethyl)-5-pyrimidinecarboxamide

[1764]¹H-NMR(DMSO-d₆): δ 0.89(3H, t, J=6.0 Hz), 1.0-1.3(2H, m),1.6-1.8(3H, m), 2.98(2H, t, J=6.8 Hz), 2.95-3.15(2H, m), 3.35(2H, dd,J=6.8 and 5.7 Hz), 4.1-4.3(2H, m), 5.66(1H, t, J=5.7 Hz), 6.59(2H, d,J=8.9 Hz), 7.15-7.25(1H, m), 7.32(1H, d, J=7.8 Hz), 7.38(2H, d, J=8.9Hz), 7.65-7.75(1H, m), 8.41(1H, s), 8.5-8.55(1H, m), 10.30(1H, s)ESI-MS(m/z): 507(M+Na)⁺, 485(M+H)⁺

[1765] Preparation 172

[1766] The following compound was obtained in substantially the samemanner as in Preparation 168.

[1767] Ethyl4-(4-methyl-1-piperidinyl)-2-(methylthio)-5-pyrimidinecarboxylate

[1768]¹H-NMR(DMSO-d₆): δ 0.92(3H, d, J=6.0 Hz), 1.0-1.3(2H, m),1.6-1.8(3H, m), 2.46(3H, s), 2.9-3.1(2H, m), 3.9-4.05(2H, m), 4.25(2H,q, J=7.1 Hz), 8.37(1H, s) ESI-MS(m/z): 318(M+Na)⁺, 296(M+H)⁺

[1769] Preparation 173

[1770] 4-(4-Methyl-1-piperidinyl)-2-(methylthio)-5-pyrimidinecarboxylicacid was obtained in substantially the same manner as in Preparation169. This compound was used in Example 329 without purification.

EXAMPLE 329

[1771] The following compound was obtained in substantially the samemanner as in Example 325.

[1772]N-(4-{Formyl[2-(2-pyridinyl)ethyl]amino}phenyl)-4-(4-methyl-1-piperidinyl)-2-(methylthio)-5-pyrimidinecarboxamide

[1773]¹H-NMR(DMSO-d₆): δ 0.89(3H, d, J=5.9 Hz), 1.0-1.3(2H, m),1.6-1.8(3H, m), 2.54(3H, s), 2.8-3.1(4H, m), 3.85-4.0(2H, m),4.0-4.2(2H, m), 6.56(2H, d, J=8.6 Hz), 6.90(2H, d, J=8.6 Hz),7.15-7.3(4H, m), 7.65-7.75(3H, m), 8.18(1H, s), 8.33(1H, s),8.45-8.5(1H, m), 10.52(1H, s)

EXAMPLE 330

[1774] The following compound was obtained in substantially the samemanner as in Example 326.

[1775]4-(4-Methyl-1-piperidinyl)-2-(methylthio)-N-(4-{[2-(2-pyridinyl)ethyl]amino}phenyl)-5-pyrimidinecarboxamide

[1776]¹H-NMR(DMSO-d₆): δ 0.88(3H, t, J=6.0 Hz), 1.0-1.3(2H, m),1.55-1.75(3H, m), 2.46(3H, s), 2.85-3.05(2H, m), 2.98(2H, t, J=7.2 Hz),3.35(2H, td, J=7.2, 5.7 Hz), 4.1-4.3(2H, m), 5.59(1H, s), 6.57(2H, d,J=8.8 Hz), 7.15-7.25(1H, m), 7.31(1H, d, J=7.7 Hz), 7.37(1H, d, J=8.8Hz), 7.65-7.8(1H, m), 8.10(1H, s), 8.5-8.55(1H, m), 10.04(1H, s)

EXAMPLE 331

[1777] To a solution of4-{2-[3-(2,5-dimethyl-1H-pyrrol-1-yl)-1H-pyrazol-1-yl]ethoxy}aniline(1.48 g) in dichloromethane (40 ml) was added triethylamine, followed bydropwise addition of a solution of4′-(trifluoromethyl)-1,1′-biphenyl-2-carbonyl chloride (1.42 g) indichloromethane (10 ml) at ambient temperature and the mixture wasstirred for 5 hours at the same temperature. The mixture was poured intowater and the separated organic layer was washed with brine, dried overmagnesium sulfate and evaporated in vacuo. The residue was purified bycolumn chromatography on silica gel eluting with hexane: ethyl acetate(2:1) to giveN-(4-{2-[3-(2,5-dimethyl-1H-pyrrol-1-yl)-1H-pyrazol-1-yl]ethoxy}phenyl)-4′-(trifluoromethyl)-1,1′-biphenyl-2-carboxamide(2.31 g) as white powder.

[1778]¹H-NMR(DMSO-d₆): δ 1.94(6H, s), 4.21(4H, s), 5.45(1H, d, J=2.3Hz), 5.73(2H, s), 6.27(1H, d, J=2.3 Hz), 7.3-7.8(12H, m), 10.21(1H, s)negative ESI-MS(m/z): 543(M−H)⁻

EXAMPLE 332

[1779] To a suspension ofN-(4-{2-[3-(2,5-dimethyl-1H-pyrrol-1-yl)-1H-pyrazol-1-yl]ethoxy}phenyl)-4′-(trifluoromethyl)-1,1′-biphenyl-2-carboxamide(2.29 g) in a mixture of ethanol (40 ml) and water (10 ml) were addedhydroxylamine hydrochloride (2.92 g) and triethylamine (851 mg) atambient temperature. The mixture was refluxed for 6 hours and evaporatedto dryness. The residue was extracted from ethyl acetate and the organiclayer was washed with brine, dried over magnesium sulfate and evaporatedin vacuo. The residue was purified by column chromatography on silicagel eluting with ethyl acetate to giveN-{4-[2-(3-amino-1H-pyrazol-1-yl)ethoxy]phenyl}-4′-(trifluoromethyl)-1,1′-biphenyl-2-carboxamide(890 mg) as a white crystal.

[1780]¹H-NMR(DMSO-d₆): δ 4.17(4H, s), 4.56(2H, brs), 5.37(1H, d, J=2.1Hz), 6.82(2H, d, J=9.0 Hz), 7.34(1H, d, J=2.1 Hz), 7.41(2H, d, J=9.0Hz), 7.5-7.7(7H, m), 7.75(2H, d, J=8.3 Hz), 10.21(1H, s)

[1781] Preparation 174

[1782] The following compound was obtained in substantially the samemanner as in Preparation 124.

[1783] 2-[5-(2,5-Dimethyl-1H-pyrrol-1-yl)-1H-pyrazol-1-yl]ethanol

[1784]¹H-NMR(DMSO-d₆): δ 1.91(6H, s), 3.6-3.7(4H, m), 4.83(1H, t, J=5.3Hz), 5.85(2H, s), 6.33(1H, d, J=1.7 Hz), 7.62(1H, d, J=1.7 Hz)

[1785] Preparation 175

[1786] The following compound was obtained in substantially the samemanner as in Preparation 125.

[1787]5-(2,5-Dimethyl-1H-pyrrol-1-yl)-1-[2-(4-nitrophenoxy)ethyl]-1H-pyrazole

[1788]¹H-NMR(DMSO-d₆): δ 1.96(6H, s), 4.04(2H, t, J=5.0 Hz), 4.48(2H, t,J=5.0 Hz), 5.89(2H, s), 6.41(1H, d, J=2.0 Hz), 7.0-7.1(2H, m), 7.67(1H,d, J=2.0 Hz), 8.15-8.25(2H, m) ESI-MS(m/z): 349(M+Na)⁺

[1789] Preparation 176

[1790] The following compound was obtained in substantially the samemanner as in Preparation 126.

[1791]4-{2-[5-(2,5-Dimethyl-1H-pyrrol-1-yl)-1H-pyrazol-1-yl]ethoxy}aniline

[1792]¹H-NMR(DMSO-d₆): δ 1.91(6H, s), 3.92(2H, t, J=5.1 Hz), 4.12(2H, t,J=5.1 Hz), 4.61(2H, brs), 5.88(2H, s), 6.37(1H, d, J=1.9 Hz),6.4-6.6(4H, m), 7.65(1H, d, J=1.9 Hz)

EXAMPLE 333

[1793] The following compound was obtained in substantially the samemanner as in Example 331.

[1794]N-(4-{2-[5-(2,5-Dimethyl-1H-pyrrol-1-yl)-1H-pyrazol-1-yl]ethoxy}phenyl)-4′-(trifluoromethyl)-1,1′-biphenyl-2-carboxamide

[1795]¹H-NMR(DMSO-d₆): δ 1.95(6H, s), 3.98(2H, t, J=4.9 Hz), 4.24(2H, t,J=4.9 Hz), 5.89(2H, s), 6.39(1H, d, J=1.9 Hz), 6.73(2H, d, J=9.0 Hz),7.38(2H, d, J=9.0 Hz), 7.45-7.7(7H, m), 7.75(2H, d, J=8.3 Hz), 10.20(1H,s) ESI-MS(m/z): 567(M+Na)⁺

EXAMPLE 334

[1796] The following compound was obtained in substantially the samemanner as in Example 332.

[1797]N-{4-[2-(5-Amino-1H-pyrazol-1-yl)ethoxy]phenyl}-4′-(trifluoromethyl)-1,1′-biphenyl-2-carboxamide

[1798]¹H-NMR(DMSO-d₆): δ 4.19(4H, s), 5.16(2H, brs), 5.27(1H, d, J=1.7Hz), 6.84(2H, d, J=9.0 Hz), 7.06(1H, d, J=1.7 Hz), 7.41(2H, d, J=9.0Hz), 7.3-7.8(8H, m), 10.29(1H, s) ESI-MS(m/z): 489(M+Na)⁺, 467(M+H)⁺

EXAMPLE 335

[1799] The following compound was obtained in substantially the samemanner as in Example 331.

[1800]N-{4-[(1H-Pyrazol-1-ylacetyl)amino]phenyl}-4′-(trifluoromethyl)-1,1′-biphenyl-2-carboxamide

[1801]¹H-NMR(DMSO-d₆): δ 4.99(2H, s), 6.25-6.3(1H, m), 7.4-7.8(4H, m),10.26(1H, s), 10.32(1H, s) ESI-MS(m/z): 487(M+Na)⁺

EXAMPLE 336

[1802] To a solution of N-(4-aminophenyl)-2-(1H-pyrazol-1-yl)acetamide(432 mg), 2-(4-methylphenyl)-1-cyclohexene-1-carboxylic acid (432 mg)and benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate(PyBOP) (1.25 g) in N,N-dimethylformamide (40 ml) was addeddiisopropylethylamine (516 mg) at ambient temperature and the mixturewas stirred at the same temperature for 24 hours. The mixture was pouredinto a mixture of ethyl acetate, water and 6N hydrochloric acid, and theseparated organic layer was washed with water and brine, dried overmagnesium sulfate and evaporated in vacuo. The residue was purified bycolumn chromatography on silica gel eluting with ethyl acetate to give2-(4-methylphenyl)-N-{4-[(1H-pyrazol-1-ylacetyl)amino]phenyl}-1-cyclohexene-1-carboxamide(625 mg) as a pale brown powder.

[1803]¹H-NMR(DMSO-d₆): δ 1.6-1.8(4H, m), 2.20(3H, s), 2.3-2.45(4H, m),4.96(2H, s), 6.26(1H, dd, J=2.3 and 1.8 Hz), 7.03(2H, d, J=8.1 Hz),7.18(2H, d, J=8.1 Hz), 7.31(2H, d, J=9.1 Hz), 7.39(2H, d, J=9.1 Hz),7.44(1H, d, J=1.8 Hz), 7.73(1H, d, J=2.3 Hz), 9.48(1H, s), 10.18(1H, s)ESI-MS(m/z): 437(M+Na)⁺

EXAMPLE 337

[1804] The following compound was obtained in substantially the samemanner as in Example 331.

[1805]N-[1-(1H-Pyrazol-1-ylacetyl)-2,3-dihydro-1H-indol-5-yl]-4′-(trifluoromethyl)-1,1′-biphenyl-2-carboxamide

[1806]¹H-NMR(DMSO-d₆): δ 3.16(2H, t, J=8.3 Hz), 4.17(2H, t, J=8.3 Hz),5.22(2H, s), 6.29(1H, dd, J=2.2 and 1.7 Hz), 7.22(1H, dd, J=8.7 and 1.7Hz), 7.46(1H, d, J=1.7 Hz), 7.5-7.7(6H, m), 7.71(1H, d, J=2.2 Hz),7.76(2H, d, J=8.6 Hz), 7.86(2H, d, J=8.6 Hz), 10.32(1H, s)

EXAMPLE 338

[1807] The following compound was obtained in substantially the samemanner as in Example 331.

[1808]4′-Methyl-N-[1-(1H-pyrazol-1-ylacetyl)-2,3-dihydro-1H-indol-5-yl]-1,1′-biphenyl-2-carboxamide

[1809]¹H-NMR(DMSO-d₆): δ 2.29(3H, s), 3.16(2H, t, J=7.6 Hz), 4.17(2H, t,J=7.6 Hz), 5.22(2H, s), 6.29(1H, dd, J=2.1 and 1.4 Hz), 7.17(2H, d,J=8.0 Hz), 7.2-7.3(1H, m), 7.32(2H, d, J=8.0 Hz), 7.4-7.55(5H, m),7.55(1H, d, J=1.4 Hz), 7.71(1H, d, J=2.1 Hz), 7.86(1H, d, J=8.7 Hz),10.21(1H, s) ESI-MS(m/z): 459(M+Na)⁺, 437(M+H)⁺

EXAMPLE 339

[1810] To a solution of 1-(1H-pyrazol-1-ylacetyl)-5-indolinamine (905mg), 4′-(dimethylamino)-1,1′-biphenyl-2-carboxylic acid (901 mg) andbenzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate(PyBOP) (2.33 g) in N,N-dimethylformamide (30 ml) was added dropwisediisopropylethylamine (966 mg) at ambient temperature and the mixturewas stirred at the same temperature for 20 hours. The mixture was pouredinto a mixture of ethyl acetate and water and the separated organiclayer was washed with water and brine, dried over magnesium sulfate andevaporated in vacuo. The residue was purified by column chromatographyon silica gel eluting with ethyl acetate to give4′-(dimethylamino)-N-[1-(1H-pyrazol-1-ylacetyl)-2,3-dihydro-1H-indol-5-yl]-1,1′-biphenyl-2-carboxamide(954 mg) as a pale yellow powder.

[1811]¹H-NMR(DMSO-d₆): δ 2.88(6H, s), 3.17(2H, t, J=8.3 Hz), 4.17(2H, t,J=8.3 Hz), 5.22(2H, s), 6.29(1H, dd, J=2.3 and 1.4 Hz), 6.70(2H, d,J=8.8 Hz), 7.29(2H, d, J=8.8 Hz), 7.25-7.55(5H, m), 7.46(1H, d, J=1.4Hz), 7.56(1H, s), 7.71(1H, d, J=2.3 Hz), 7.86(1H, d, J=8.6 Hz),10.14(1H, s) ESI-MS(m/z): 488(M+Na)⁺

EXAMPLE 340

[1812] The following compound was obtained in substantially the samemanner as in Example 339.

[1813]2-(4-Methylphenyl)-N-[1-(1H-pyrazol-1-ylacetyl)-2,3-dihydro-1H-indol-5-yl]-1-cyclohexene-1-carboxamide

[1814]¹H-NMR(DMSO-d₆): δ 1.6-1.8(4H, m), 2.21(3H, s), 2.25-2.4(4H, m),3.11(2H, t, J=8.5 Hz), 4.13(2H, t, J=8.5 Hz), 5.20(2H, s), 6.28(1H, dd,J=2.0 and 1.7 Hz), 7.04(2H, d, J=8.1 Hz), 7.0-7.1(1H, m), 7.17(2H, d,J=8.1 Hz), 7.40(1H, s), 7.45(1H, d, J=1.7 Hz), 7.69(1H, d, J=2.0 Hz),7.77(1H, d, J=8.6 Hz), 9.48(1H, s)

EXAMPLE 341

[1815] The following compound was obtained in substantially the samemanner as in Example 339.

[1816]2-[4-(Dimethylamino)phenyl]-N-[1-(1H-pyrazol-1-ylacetyl)-2,3-dihydro-1H-indol-5-yl]-1-cyclohexene-1-carboxamide

[1817]¹H-NMR(DMSO-d₆): δ 1.6-1.8(4H, m), 2.3-2.45(4H, m), 2.82(6H, s),3.12(2H, t, J=8.6 Hz), 4.13(2H, t, J=8.6 Hz), 5.20(2H, s), 6.28(1H, dd,J=2.2 and 1.6 Hz), 6.58(2H, d, J=8.8 Hz), 7.09(1H, dd, J=8.6 and 1.3Hz), 7.13(2H, d, J=8.8 Hz), 7.42(1H, d, J=1.6 Hz), 7.69(1H, d, J=2.2Hz), 7.78(1H, d, J=8.6 Hz), 9.41(1H, s) negative ESI-MS(m/z): 468(M−H)⁻

[1818] Preparation 177

[1819] To a solution of 5-nitroindoline (11.72 g) and triethylamine(8.67 g) in N,N-dimethylformamide (150 ml) was added dropwisechloroacetyl chloride (8.06 g) at 5° C. and the mixture was stirred atambient temperature for 20 hours. The mixture was poured into a mixtureof ethyl acetate and water and the separated organic layer was washedwith water and brine, dried over magnesium sulfate and evaporated invacuo. The residue was triturated with ethyl acetate and collected byfiltration to give 1-(chloroacetyl)-5-nitroindoline (14.66 g) as ayellow crystal.

[1820]¹H-NMR(DMSO-d₆): δ 3.28(2H, t, J=8.6 Hz), 4.25(2H, t, J=8.6 Hz),4.64(2H, s), 8.1-8.2(3H, m) ESI-MS(m/z): 263(M+Na)⁺

[1821] Preparation 178

[1822] To a solution of 1-(chloroacetyl)-5-nitroindoline (4.81 g) inN,N-dimethylformamide (80 ml) was added 1,2,4-triazole sodium derivative(purity 90%)(2.18 g) at ambient temperature and the mixture was stirredat 50° C. for 6 hours. The mixture was poured into a mixture of ethylacetate and water and the separated organic layer was washed with waterand brine, dried over magnesium sulfate and evaporated in vacuo. Theresidue was purified by column chromatography on silica gel eluting withhexane: ethyl acetate (1:2) to give5-nitro-1-(1H-1,2,4-triazol-1-ylacetyl)indoline (2.63 g) as a yellowpowder.

[1823]¹H-NMR(DMSO-d₆): δ 3.33(2H, t, J=8.7 Hz), 4.34(2H, t, J=8.7 Hz),5.47(2H, s), 8.03(1H, s), 8.1-8.2(3H, m), 8.51(1H, s) negativeESI-MS(m/z): 272(M−H)⁻

[1824] Preparation 179

[1825] To a solution of 5-nitro-1-(1H-1,2,4-triazol-1-ylacetyl)indoline(2.62 g) in N,N-dimethylformamide (50 ml) was added 5% palladium oncarbon (50% wet) (1 g) and the mixture was hydrogenated for 4 hours at45° C. The catalyst was removed by filtration and washed withN,N-dimethylformamide (10 ml). The filtrate containing1-(1H-1,2,4-triazol-1-ylacetyl)-5-indolinamine was used to next stepwithout further purification.

EXAMPLE 342

[1826] The following compound was obtained in substantially the samemanner as in Example 339.

[1827]2-(4-Methylphenyl)-N-[1-(1H-1,2,4-triazol-1-ylacetyl)-2,3-dihydro-1H-indol-5-yl]-1-cyclohexene-1-carboxamide

[1828]¹H-NMR(DMSO-d₆): δ 1.6-1.85(4H, m), 2.21(3H, s), 2.3-2.45(4H, m),3.13(2H, t, J=8.4 Hz), 4.15(2H, t, J=8.4 Hz), 5.33(2H, s), 7.02(2H, d,J=8.1 Hz), 7.04(1H, d, J=8.6 Hz), 7.17(2H, d, J=8.1 Hz), 7.41(1H, s),7.76(1H, d, J=8.6 Hz), 7.99(1H, s), 8.48(1H, s), 9.49(1H, s)ESI-MS(m/z): 464(M+Na)⁺

EXAMPLE 343

[1829] To a solution ofN-(2,3-dihydro-1H-indol-5-yl)-4′-(trifluoromethyl)-1,1′-biphenyl-2-carboxamide(765 mg), 1H-tetrazol-1-ylacetic acid (256 mg) andbenzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate(PyBOP) (1.25 g) in N,N-dimethylformamide (40 ml) was added dropwisediisopropylethylamine (966 mg) at ambient temperature and the mixturewas stirred at the same temperature for 20 hours. The mixture was pouredinto a mixture of ethyl acetate and water and the separated organiclayer was washed with water and brine, dried over magnesium sulfate andevaporated in vacuo. The residue was purified by column chromatographyon silica gel eluting with hexane:ethyl acetate (1:2) to giveN-[1-(1H-tetrazol-1-ylacetyl)-2,3-dihydro-1H-indol-5-yl]-4′-(trifluoromethyl)-1,1′-biphenyl-2-carboxamide(810 mg) as a white crystal.

[1830]¹H-NMR(DMSO-d₆): δ 3.20(2H, t, J=8.3 Hz), 4.23(2H, t, J=8.3 Hz),5.72(2H, s), 7.23(1H, dd, J=8.7 and 1.7 Hz), 7.5-7.9(10H, m), 9.37(1H,s), 10.33(1H, s) ESI-MS(m/z): 515(M+Na)⁺

[1831] Preparation 180

[1832] The following compound was obtained in substantially the samemanner as in Preparation 130.

[1833] 5-Nitro-1-(1H-tetrazol-1-ylacetyl)indoline

[1834]¹H-NMR(DMSO-d₆): δ 3.35(2H, t, J=8.5 Hz), 4.37(2H, t, J=8.5 Hz),5.82(2H, s), 8.05-8.2(3H, m), 9.38(1H, s)

[1835] Preparation 181

[1836] 1-(1H-Tetrazol-1-ylacetyl)-5-indolinamine was obtained insubstantially the same manner as in Preparation 179. This compound wasused in Example 344 without purification.

EXAMPLE 344

[1837] The following compound was obtained in substantially the samemanner as in Example 339.

[1838]4′-(Dimethylamino)-N-[1-(1H-tetrazol-1-ylacetyl)-2,3-dihydro-1H-indol-5-yl]-1,1′-biphenyl-2-carboxamide

[1839]¹H-NMR(DMSO-d₆): δ 2.88(6H, s), 3.21(2H, t, J=8.5 Hz), 4.23(2H, t,J=8.5 Hz), 5.75(2H, s), 6.70(2H, d, J=8.7 Hz), 7.28(2H, t, J=8.7 Hz),7.3-7.6(6H, m), 7.83(1H, d, J=8.7 Hz), 9.90(1H, s), 10.22(1H, s)ESI-MS(m/z): 490(M+Na)⁺, 468(M+H)⁺

EXAMPLE 345

[1840] The following compound was obtained in substantially the samemanner as in Example 339.

[1841]2-(4-Methylphenyl)-N-[1-(1H-tetrazol-1-ylacetyl)-2,3-dihydro-1H-indol-5-yl]-1-cyclohexene-1-carboxamide

[1842]¹H-NMR(DMSO-d₆): δ 1.6-1.8(4H, m), 2.21(3H, s), 2.3-2.4(4H, m),3.15(2H, t, J=8.4 Hz), 4.19(2H, t, J=8.4 Hz), 5.70(2H, s), 7.04(2H, d,J=8.1 Hz), 7.0-7.1(1H, m), 7.17(2H, d, J=8.1 Hz), 7.43(1H, s), 7.75(1H,d, J=8.7 Hz), 9.35(1H, s), 9.2(1H, s)

EXAMPLE 346

[1843] The following compound was obtained in substantially the samemanner as in Example 200.

[1844]2-(4-Methylphenyl)-N-[2-(1H-pyrazol-1-ylacetyl)-2,3-dihydro-1H-isoindol-5-yl]-1-cyclohexene-1-carboxamide

[1845]¹H-NMR(DMSO-d₆): δ 1.6-1.8(4H, m), 2.27(3H, s), 2.3-2.45(4H, m),4.5-4.6(2H, m), 4.7-4.8(2H, m), 5.13(2H, s), 6.25-6.3(1H, dd, J=2.2 and1.6 Hz), 7.05-7.3(7H, m), 7.44(1H, d, J=1.6 Hz), 7.68(1H, d, J=2.2 Hz),9.60(1H, s) ESI-MS(m/z): 463(M+Na)⁺, 441(M+H)⁺

EXAMPLE 347

[1846] The following compound was obtained in substantially the samemanner as in Example 200.

[1847]N-[2-(1H-Pyrazol-1-ylacetyl)-2,3-dihydro-1H-isoindol-5-yl]-2-[4-(trifluoromethyl)phenyl]-1-cyclohexene-1-carboxamide

[1848]¹H-NMR(DMSO-d₆): δ 1.6-1.8(4H, m), 2.3-2.45(4H, m), 4.5-4.6(2H,m), 4.8-4.9(2H, m), 5.13(2H, s), 6.27(1H, dd, J=2.3 and 1.7 Hz),7.18(2H, s), 7.44(1H, d, J=1.7 Hz), 7.48(2H, d, J=8.5 Hz), 7.63(2H, d,J=8.5 Hz), 7.68(1H, d, J=2.3 Hz), 9.73 and 9.75(total 1H, s)ESI-MS(m/z): 517(M+Na)⁺, 495(M+H)⁺

EXAMPLE 348

[1849] The following compound was obtained in substantially the samemanner as in Example 200.

[1850]2-[4-(Dimethylamino)phenyl]-N-[2-(1H-pyrazol-1-ylacetyl)-2,3-dihydro-1H-isoindol-5-yl]-1-cyclohexene-1-carboxamide

[1851]¹H-NMR(DMSO-d₆): δ 1.6-1.8(4H, m), 2.3-2.45(4H, m), 2.84(6H, s),4.5-4.6(2H, m), 4.8-4.9(2H, m), 5.13(2H, s), 6.27(1H, dd, J=2.0 and 1.7Hz), 6.58(2H, d, J=8.7 Hz), 7.14(2H, d, J=8.7 Hz), 7.1-7.3(2H, m),7.44(1H, d, J=1.7 Hz), 7.52(1H, s), 7.68(1H, d, J=2.0 Hz), 9.53(1H, s)negative ESI-MS(m/z): 468(M−H)⁻

EXAMPLE 349

[1852] A mixture of 6-methyl-2-(4-methyl-1-piperidinyl)nicotinic acid(7.4 g), 1-acetyl-2,3-dihydro-1H-indol-5-ylamine (5.3 g),1-hydroxybenzotriazole hydrate (4.84 g) and1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide (4.9 g) inN,N-dimethylformamide (50 ml) was stirred at ambient temperature for 15hours. The reaction mixture was poured into a mixture of ethyl acetateand water, and the organic layer was washed with brine and dried overmagnesium sulfate. The solvent was concentrated in vacuo and theprecipitate was collected by filtration to giveN-(1-acetyl-2,3-dihydro-1H-indol-5-yl)-6-methyl-2-(4-methyl-1-piperidinyl)nicotinamide(10.15 g).

[1853]¹H-NMR(DMSO-d₆): δ 0.89(3H, d J=6.18 Hz), 1.11-1.28(2H, m),1.42-1.65(3H, m), 2.14(3H, s), 2.39(3H, s), 2.74-2.86(2H, m), 3.14(2H, tJ=8.32 Hz), 3.14(2H, t J=8.38 Hz), 3.61-3.68(2H, m), 4.08(2H, t J=8.32Hz), 6.82(1H, d J=7.60 Hz), 7.39(1H, dd J=1.74 Hz, 8.62 Hz), 7.72(1H,s), 7.74(1H, d J=7.60 Hz), 7.99(1H, d J=8.62 Hz), 10.48(1H, s)

[1854] Preparation 182

[1855] A mixture ofN-(1-acetyl-2,3-dihydro-1H-indol-5-yl)-6-methyl-2-(4-methyl-1-piperidinyl)nicotinamide(10.1 g) and 6N hydrochloric acid (28 ml) in methanol (40 ml) andtetrahydrofuran (40 ml) was refluxed under stirring for 9 hours. Thereaction mixture was evaporated in vacuo and the residue was dissolvedin a mixture of ethyl acetate and water and adjusted to pH 8.0 with 20%potassium carbonate solution. The organic layer was washed with brineand dried over magnesium sulfate. The solvent was concentrated in vacuoand the precipitate was collected by filtration to giveN-(2,3-dihydro-1H-indol-5-yl)-6-methyl-2-(4-methyl-1-piperidinyl)nicotinamide(7.9 g).

[1856]¹H-NMR(DMSO-d₆): δ 0.93(3H, d J=6.22 Hz), 1.17-1.30(2H, m),1.46-1.64(3H, m), 2.38(3H, s), 2.74-2.94(4H, m), 3.34-3.44(2H, m),3.60-3.67(2H, m), 5.35(1H, s), 6.46(1H, d J=8.24 Hz), 6.82(1H, d J=7.64Hz), 7.20(1H, dd J=2.04 Hz, 8.24 Hz), 7.46(1H, s), 7.74(1H, d J=7.64Hz), 10.24(1H, s)

EXAMPLE 350

[1857] The following compound was obtained in substantially the samemanner as in Example 31.

[1858] tert-Butyl6-{2-[5-({[6-methyl-2-(4-methyl-1-piperidinyl)-3-pyridinyl]carbonyl}amino)-2,3-dihydro-1H-indol-1-yl]-2-oxoethyl}-2-pyridinylcarbamate

[1859]¹H-NMR(DMSO-d₆): δ 0.89(3H, d J=6.14 Hz), 1.14-1.26(2H, m),1.42-1.65(2H, m), 1.46(9H, s), 2.39(3H, s), 2.75-2.86(2H, m), 3.18(2H, tJ=8.26 Hz), 3.61-3.63(2H, m), 3.86(2H, s), 4.28(2H, t J=8.26 Hz),6.82(1H, d J=7.70 Hz), 6.96-7.00(1H, m), 7.38(1H, dd J=1.76 Hz, 8.66Hz), 7.64-7.76(4H, m), 7.91(1H, d J=8.66 Hz), 9.66(1H, s), 10.48(1H, s)

EXAMPLE 351

[1860] The following compound was obtained in substantially the samemanner as in Example 32.

[1861]N-{1-[(6-Amino-2-pyridinyl)acetyl]-2,3-dihydro-1H-indol-5-yl}-6-methyl-2-(4-methyl-1-piperidinyl)nicotinamide

[1862]¹H-NMR(DMSO-d₆): δ 0.89(3H, d J=6.12 Hz), 1.13-1.26(2H, m),1.48-1.65(3H, m), 2.39(3H, s), 2.74-2.86(2H, m), 3.15(2H, t J=8.26 Hz),3.60-3.63(2H, m), 3.68(2H, s), 4.20(2H, t J=8.26 Hz), 5.87(2H, s),6.31(1H, d J=8.02 Hz), 6.43(1H, d J=7.14 Hz), 6.82(1H, d J=7.64 Hz),7.28-7.41(2H, m), 7.72-7.76(2H, m), 8.00(1H, d J=8.66 Hz), 10.48(1H, s)ESI-MS(m/z): 507(M+Na)⁺, 485(M+1)⁺

EXAMPLE 352

[1863] The following compound was obtained in substantially the samemanner as in Example 349.

[1864]2-(Isopropylamino)-6-methyl-N-[1-(2-pyridinylacetyl)-2,3-dihydro-1H-indol-5-yl]nicotinamide

[1865]¹H-NMR(DMSO-d₆): δ 1.17(6H, d J=6.46 Hz), 2.34(3H, s), 3.16(2H, tJ=8.30 Hz), 3.98(2H, s), 4.08-4.34(3H, m), 6.47(1H, d J=7.86 Hz),7.25-7.31(1H, m), 7.36(2H, d J=7.94 Hz), 7.63(1H, s), 7.72-7.80(1H, m),7.98(2H, d J=7.94 Hz), 8.09(1H, d J=7.36 Hz), 8.49-8.51(1H, s), 9.99(1H,s) ESI-MS(m/z): 452(M+Na)⁺, 430(M+1)⁺

EXAMPLE 353

[1866] The following compound was obtained in substantially the samemanner as in Example 349.

[1867]2-(Cyclohexylamino)-6-methyl-N-[1-(2-pyridinylacetyl)-2,3-dihydro-1H-indol-5-yl]nicotinamide

[1868]¹H-NMR(DMSO-d₆): δ 1.47-1.75(8H, m), 1.89-1.99(2H, m), 2.33(3H,s), 3.16(2H, t J=8.26 Hz), 4.01(2H, s), 3.90-4.09(1H, m), 4.22(2H, tJ=8.26 Hz), 6.46(1H, d J=7.88 Hz), 7.2-7.31(1H, m), 7.37(2H, d J=7.78Hz), 7.62(1H, d J=1.20 Hz), 7.72-7.77(1H, m), 7.98(2H, d J=7.78 Hz),8.25(1H, d J=7.62 Hz), 8.49-8.51(1H, m), 9.98(1H, s) ESI-MS(m/z):492(M+Na)⁺, 470(M+1)⁺

EXAMPLE 354

[1869] The following compound was obtained in substantially the samemanner as in Example 349.

[1870]2-(Ethylmethylamino)-6-methyl-N-[1-(2-pyridinylacetyl)-2,3-dihydro-1H-indol-5-yl]nicotinamide

[1871]¹H-NMR(DMSO-d₆): δ 1.06(3H, t J=6.96 Hz), 2.35(3H, s), 2.86(3H,s), 3.16(2H, t J=8.28 Hz), 3.43(2H, q J=6.96 Hz), 4.01(2H, s), 4.21(2H,t J=8.28 Hz), 6.62(1H, d J=7.56 Hz), 7.28-7.42(3H, m), 7.56(1H, d J=7.50Hz), 7.67(1H, s), 7.74-7.78(1H, m), 7.97(1H, d J=8.68 Hz), 8.49-8.51(1H,m), 10.31(1H, s) ESI-MS(m/z): 452(M+Na)⁺, 430(M+1)⁺

EXAMPLE 355

[1872] The following compound was obtained in substantially the samemanner as in Example 349.

[1873]2-(Diethylamino)-6-methyl-N-[1-(2-pyridinylacetyl)-2,3-dihydro-1H-indol-5-yl]nicotinamide

[1874]¹H-NMR(DMSO-d₆): δ 1.05(6H, t J=6.88 Hz), 2.37(3H, s), 3.16(2H, tJ=8.22 Hz), 3.25-3.35(4H, m), 4.00(2H, s), 4.21(2H, t J=8.22 Hz),6.70(1H, d J=7.62 Hz), 7.26-7.43(3H, m), 7.64-7.77(3H, m), 7.99(1H, ddJ=8.70 Hz), 8.49-8.51(1H, m), 10.71(1H, s) ESI-MS (m/z): 466 (M+Na)⁺,444 (M+1)⁺

EXAMPLE 356

[1875] The following compound was obtained in substantially the samemanner as in Example 358 as mentioned below.

[1876]N-(1-{[6-(Acetylamino)-2-pyridinyl]methyl}-2,3-dihydro-1H-indol-5-yl)-6-methyl-2-(4-methyl-1-piperidinyl)nicotinamide

[1877]¹H-NMR(DMSO-d₆): δ 0.90(3H, d J=6.20 Hz), 1.13-1.30(2H, m),1.49-1.66(3H, m), 1.99(3H, s), 2.39(3H, s), 2.75-2.86(2H, m), 2.94(2H, tJ=7.86 Hz), 3.37(2H, t J=7.86 Hz), 3.61-3.67(2H, m), 4.26(2H, s),6.51(1H, d J=8.40 Hz), 6.82(1H, d J=7.66 Hz), 7.11(1H, d J=7.36 Hz),7.26(1H, dd J=1.80 Hz, 8.40 Hz), 7.51(1H, d J=1.38 Hz), 7.70-7.78(2H,m), 7.98(1H, d J=8.18 Hz), 10.30(1H, s), 10.52(1H, s) ESI-MS(m/z): 521(M+Na)⁺, 499 (M+1)⁺

EXAMPLE 357

[1878] A mixture ofN-(1-{[6-(acetylamino)-2-pyridinyl]methyl}-2,3-dihydro-1H-indol-5-yl)-6-methyl-2-(4-methyl-1-piperidinyl)nicotinamide(485 mg) and 6N hydrochloric acid (1 ml) in methanol (10 ml) andtetrahydrofuran (10 ml) was refluxed under stirring for 5 hours. Thereaction mixture was evaporated in vacuo and the residue was dissolvedin a mixture of ethyl acetate and water and adjusted to PH 8.0 with 20%potassium carbonate solution. The organic layer was washed with brineand dried over magnesium sulfate. The solvent was concentrated in vacuoand the precipitate was collected by filtration to giveN-{1-[(6-amino-2-pyridinyl)methyl]-2,3-dihydro-1H-indol-5-yl}-6-methyl-2-(4-methyl-1-piperidinyl)nicotinamide(370 mg).

[1879]¹H-NMR(DMSO-d₆): δ 0.90(3H, d J=6.20 Hz), 1.17-1.30(2H, m),1.43-1.67(3H, m), 2.38(3H, s), 2.52-2.80(2H, m), 2.92(2H, t J=7.98 Hz),3.32-3.41(2H, m), 3.61-3.67(2H, m), 4.08(2H, s), 5.90(2H, s), 6.32(1H, dJ=8.08 Hz), 6.41(1H, dd J=4.34 Hz, 7.66 Hz), 6.81(1H, d J=7.56 Hz),7.22-7.36(2H, m), 7.48(1H, d J=1.84 Hz), 7.74(1H, d J=7.56 Hz),10.28(1H, s) ESI-MS(m/z): 579(M+Na)⁺, 457(M+1)⁺

EXAMPLE 358

[1880] A mixture ofN-(2,3-dihydro-1H-indol-5-yl)-6-methyl-2-(4-methyl-1-piperidinyl)nicotinamide(525 mg), 2-pyridinecarboxaldehyde (193 mg) and sodiumtriacetoxyborohydride (952 mg) in chloroform (20 ml) was stirred atambient temperature for 15 hours. A water (10 ml) was added to areaction mixture and adjusted to PH 8.5 with 10% potassium carbonatesolution and stirred at ambient temperature for 30 minutes. The organiclayer was washed with brine and dried over magnesium sulfate. Thesolvent was evaporated in vacuo and the residue was chromatographed onsilica gel eluting with ethyl acetate:n-hexane (6:4 v/v). The elutedfractions containing the desired product were collected and the solventwas evaporated in vacuo and the residue was recrystallized from amixture of diisopropyl ether and n-hexane to give6-methyl-2-(4-methyl-1-piperidinyl)-N-[1-(2-pyridinylmethyl)-2,3-dihydro-1H-indol-5-yl]nicotinamide(295 mg).

[1881]¹H-NMR(DMSO-d₆): δ 0.89(3H, d J=6.16 Hz), 1.18-1.29(2H, m),1.43-1.66(3H, m), 2.39(3H, s), 2.75-2.97(4H, m), 3.34-3.42(2H, m),3.61-3.67(2H, m), 4.35(2H, s), 6.51(1H, d J=8.42 Hz), 6.82(1H, d J=7.66Hz), 7.25-7.34(2H, m), 7.41(1H, d J=7.80 Hz), 7.51(1H, s), 7.79-7.81(2H,m), 8.53-8.55(1H, m), 10.31(1H, s) ESI-MS(m/z): 464(M+Na)⁺, 442(M+1)⁺

[1882] Preparation 183

[1883] A solution of chloroacetylchoride (967 mg) in tetrahydrofuran (5ml) was dropwise added to a mixture ofN-(2,3-dihydro-1H-indol-5-yl)-6-methyl-2-(4-methyl-1-piperidinyl)nicotinamide(2.5 g) and triethylamine (1.73 mg) in tetrahydrofuran (50 ml) at 5-20°C. with stirring and the resultant mixture was stirred at ambienttemperature for 15 hours. The reaction mixture was poured into a mixtureof ethyl acetate and water, and the organic layer was washed with brineand dried over magnesium sulfate. The solvent was evaporated in vacuoand the residue was chromatographed on silica gel eluting with ethylacetate and n-hexane (6:4). The fraction was concentrated in vacuo andthe precipitate was collected by filtration to giveN-(1-chloroacetyl-2,3-dihydro-1H-indol-5-yl)-6-methyl-2-(4-methyl-1-piperidinyl)nicotinamide.

[1884]¹H-NMR(DMSO-d₆): δ 0.88 (3H, d J=6.08 Hz), 1.16-1.23 (2H, m),1.47-1.51 (1H, m), 1.60-1.63 (2H, m), 2.39 (3H, s), 2.78-2.83 (2H, m),3.19 (2H, t J=8.36 Hz), 3.64-3.67 (2H, m), 4.14 (2H, t J=8.36 Hz), 4.52(2H, s), 6.82 (1H, d J=7.60 Hz), 7.43 (1H, d J=8.68 Hz), 7.74 (1H, dJ=7.60 Hz), 7.76 (1H, s), 7.99 (1H, d J=8.68 Hz), 10.51 (1H, s)

EXAMPLE 359

[1885] A mixture of imidazole (150 mg) and potassium tert-butoxide (247mg) in N,N-dimethylformamide (10 ml) was stirred at ambient temperaturefor 30 minutes. AN-(1-chloroacetyl-2,3-dihydro-1H-indol-5-yl)-6-methyl-2-(4-methyl-1-piperidinyl)nicotinamide(470 mg) was added to a above mixture and the resultant mixture wasstirred at 65-70° C. for 6 hours. The reaction mixture was poured into amixture of ethyl acetate and water, and the organic layer was washedwith brine and dried over magnesium sulfate. The solvent wasconcentrated in vacuo and the precipitate was collected by filtration togiveN-[1-(1H-imidazol-1-ylacetyl)-2,3-dihydro-1H-indol-5-yl]-6-methyl-2-(4-methyl-1-piperidinyl)nicotinamide(270 mg).

[1886]¹H-NMR(DMSO-d₆): δ 0.88(3H, d J=6.00 Hz), 1.17-1.19(2H, m),1.48(1H, m), 1.60-1.63(2H, m), 2.78-2.83(2H, m), 3.32(2H, t J=7.36 Hz),3.64-3.67(2H, m), 4.18(2H, t J=7.36 Hz), 5.10(2H, s), 6.81(1H, d J=7.24Hz), 6.90(1H, s), 7.01(1H, s), 7.40(1H, d J=7.60 Hz), 7.58(1H, s),7.73(1H, d J=7.24 Hz), 7.78(1H, s), 7.95(1H, d J=7.60 Hz), 10.50(1H, s)ESI-MS (m/z): 481(M+Na)⁺, 459 (M+1)⁺

EXAMPLE 360

[1887] A mixture ofN-(1-acetyl-2,3-dihydro-1H-indol-5-yl)-6-methyl-2-(4-methyl-1-piperidinyl)nicotinamide(470 mg) and 1,2,4-triazole sodium salt (140 mg) inN,N-dimethylformamide (10 ml) was stirred at 65-70° C. for 7 hours. Thereaction mixture was poured into a mixture of ethyl acetate and water,and the organic layer was washed with brine and dried over magnesiumsulfate. The solvent was concentrated in vacuo and the precipitate wascollected by filtration to give6-methyl-2-(4-methyl-1-piperidinyl)-N-[1-(1H-1,2,4-triazol-1-ylacetyl)-2,3-dihydro-1H-indol-5-yl]nicotinamide(336 mg).

[1888]¹H-NMR(DMSO-d₆): δ 0.88(3H, d J=6.10 Hz), 1.10-1.27(2H, m),1.45-1.64(3H, m), 2.39(3H, s), 2.73-2.89(2H, m), 3.23(2H, t J=8.24 Hz),3.62-3.69(2H, m), 4.22(2H, t J=8.24 Hz), 5.38(2H, s), 6.81(1H, d J=7.64Hz), 7.41(1H, dd J=1.70 Hz, 8.70 Hz), 7.73(1H, d J=7.64 Hz), 7.77(1H,s), 7.93(1H, d J=8.70 Hz), 8.01(1H, s), 8.51(1H, s), 10.50(1H, s)ESI-MS(m/z): 482(M+Na)⁺, 460(M+1)⁺

EXAMPLE 361

[1889] The following compound was obtained in substantially the samemanner as in Example 349.

[1890]N-(1-Acetyl-2,3-dihydro-1H-indol-5-yl)-2-isopropoxy-4-methylbenzamide

[1891]¹H-NMR(DMSO-d₆): δ 1.39 (6H, d J=6.00 Hz), 2.14 (3H, s), 2.36 (3H,s), 3.15 (2H, t J=8.40 Hz), 4.08 (2H, t J=8.40 Hz), 4.78-4.84 (1H, m),6.89 (1H, d J=7.68 Hz), 7.04 (1H, s), 7.37 (1H, dd J=1.04 Hz, 8.68 Hz),7.67 (1H, d J=1.04 Hz), 7.72 (1H, d J=7.68 Hz), 7.99 (1H, d J=8.68 Hz),10.06 (1H, s)

[1892] Preparation 184

[1893] The following compound was obtained in substantially the samemanner as in Preparation 182.

[1894] N-(2,3-Dihydro-1H-indol-5-yl)-2-isopropoxy-4-methylbenzamide

[1895]¹H-NMR(DMSO-d₆): δ 1.39 (6H, d J=6.00 Hz), 2.35 (3H, s), 2.91 (2H,t J=8.26 Hz), 4.75-4.87 (1H, m), 5.36 (1H, s), 6.49 (1H, d J=8.24 Hz),6.88 (1H, d J=7.92 Hz),7.02 (1H, s), 7.20 (1H, dd J=1.92 Hz, 8.24 Hz),7.43 (1H, s), 7.77 (1H, d J=7.92 Hz), 9.84 (1H, s)

[1896] Preparation 185

[1897] The following compound was obtained in substantially the samemanner as in Preparation 183.

[1898]N-[1-(Chloroacetyl)-2,3-dihydro-1H-indol-5-yl]-2-isopropoxy-4-methylbenzamide

[1899]¹H-NMR(DMSO-d₆): δ 1.39 (6H, d J=6.00 Hz), 2.36 (3H, s), 3.19 (2H,t J=8.22 Hz), 4.15 (2H, t J=8.22 Hz), 4.52 (2H, s), 4.74-4.86 (1H, m),6.89 (1H, d J=7.74 Hz), 7.04 (1H, s), 7.42 (1H, dd J=1.54 Hz, 8.62 Hz),7.70-7.73 (2H, m), 7.99 (1H, d J=8.62 Hz), 10.08 (1H, s)

EXAMPLE 362

[1900] The following compound was obtained in substantially the samemanner as in Example 360.

[1901]2-Isopropoxy-4-methyl-N-[1-(1H-1,2,4-triazol-1-ylacetyl)-2,3-dihydro-1H-indol-5-yl]benzamide

[1902]¹H-NMR(DMSO-d₆): δ 1.39 (6H, d J=6.00 Hz), 2.36 (3H, s), 3.24 (2H,t J=8.28 Hz), 4.22 (2H, t J=8.28 Hz), 4.74-4.86 (1H, m), 5.38 (1H, s),6.89 (1H, d J=7.74 Hz), 7.04 (1H, s), 7.40 (1H, dd J=1.70 Hz, 8.70 Hz),7.71 (1H, d J=7.74 Hz), 7.73 (1H, s), 7.93 (1H, d J=8.70 Hz), 8.00 (1H,s), 8.51 (1H, s), 10.08 (1H, s)

[1903] Preparation 186

[1904] The following compound was obtained in substantially the samemanner as in Preparation 40.

[1905] tert-Butyl5-({[6-methyl-2-(4-thiomorpholinyl)-3-pyridinyl]carbonyl}amino)-1-indolinecarboxylate

[1906]¹H-NMR(DMSO-d₆): δ 1.51 (9H, s), 2.40 (3H, s), 2.62-2.66 (4H, m),3.07 (2H, t J=8.36 Hz), 3.51-3.55 (4H, m), 3.91 (2H, t J=8.36 Hz), 6.84(1H, d J=7.64 Hz), 7.42 (1H, d J=6.46 Hz), 7.66-7.72 (3H, m), 10.26 (1H,s)

[1907] Preparation 187

[1908] The following compound was obtained in substantially the samemanner as in Preparation 41.

[1909]N-(2,3-Dihydro-1H-indol-5-yl)-6-methyl-2-(4-thiomorpholinyl)nicotinamide

[1910]¹H-NMR(DMSO-d₆): δ 2.39 (3H, s), 2.63-2.68 (4H, m), 2.90 (2H, tJ=8.30 Hz), 3.33-3.44 (2H, m), 3.50-3.55 (4H, m), 5.35 (1H, s), 6.47(1H, d J=8.26 Hz), 6.83 (1H, d J=7.60 Hz), 7.20 (1H, dd J=1.94 Hz, 8.26Hz), 7.45 (1H, d J=1.94 Hz), 7.69 (1H, d J=7.60 Hz), 10.02 (1H, s)

EXAMPLE 363

[1911] The following compound was obtained in substantially the samemanner as in Example 26.

[1912]6-Methyl-N-[1-(2-pyridinylacetyl)-2,3-dihydro-1H-indol-5-yl]-2-(4-thiomorpholinyl)nicotinamide

[1913]¹H-NMR(DMSO-d₆): δ 2.40 (3H, s), 2.62-2.66 (4H, m), 3.17 (2H, tJ=8.38 Hz), 3.51-3.56 (4H, m), 3.98 (2H, s), 4.22 (2H, t J=8.38 Hz),6.84 (1H, d J=7.68 Hz), 7.25-7.45 (3H, m), 7.69-7.80 (3H, m), 7.99 (1H,d J=8.66 Hz), 10.32 (1H, s) negative ESI-MS(m/z): 472 (M−1)⁻

[1914] Preparation 188

[1915] A mixture of 2-chloro-6-methylnicotinic acid (1.72 g),1-(2-(2-pyridinyl)ethyl)-5-indolinamine (2.4 g), 1-hydroxybenzotriazolehydrate (1.61 g) and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide(1.63 g) in N,N-dimethylformamide (100 ml) was stirred at ambienttemperature for 15 hours. The reaction mixture was poured into a mixtureof ethyl acetate and water, and the organic layer was washed with brineand dried over magnesium sulfate. The solvent was evaporated in vacuoand the residue was chromatographed on silica gel eluting with ethylacetate:n-hexane (8:2 v/v) The eluted fractions containing the desiredproduct were collected and the solvent was concentrated in vacuo and theprecipitate was collected by filtration to give2-chloro-6-methyl-N-{1-[2-(2-pyridinyl)ethyl]-2,3-dihydro-1H-indol-5-yl}nicotinamide(2.81 g).

[1916]¹H-NMR(DMSO-d₆): δ 2.50 (3H, s), 2.73-3.02 (4H, m), 3.30-3.45 (4H,m), 6.49 (1H, d J=8.44 Hz), 7.21-7.41 (5H, m), 7.67-7.71 (1H, m), 7.88(1H, d J=7.64 Hz), 8.50-8.53 (1H, m), 10.18 (1H, s)

EXAMPLE 364

[1917] A mixture of2-chloro-6-methyl-N-{1-[2-(2-pyridinyl)ethyl]-2,3-dihydro-1H-indol-5-yl}nicotinamide(590 mg) and 4-methylpiperidine(0.71 ml) in tetrahydrofuran (10 ml) wasrefluxed under stirring for 8 hours. The reaction mixture was pouredinto a mixture of ethyl acetate and water, and the organic layer waswashed with brine and dried over magnesium sulfate. The solvent wasevaporated in vacuo and the residue was chromatographed on silica geleluting with ethyl acetate n-hexane (7:3 v/v). The eluted fractionscontaining the desired product were collected and the solvent wasevaporated in vacuo and the residue was recrystallized from a mixture ofether and n-hexane to give6-methyl-2-(4-methyl-1-piperidinyl)-N-{1-[2-(2-pyridinyl)ethyl]-2,3-dihydro-1H-indol-5-yl}nicotinamide(375 mg).

[1918]¹H-NMR(DMSO-d₆): δ 0.90 (3H, d J=6.10 Hz), 1.18-1.30 (2H, m)1.48-1.66 (3H, m), 2.40 (3H, s), 2.75-3.02 (6H, m), 3.22-3.45 (4H, m),3.60-3.67 (2H, m), 6.49 (1H, d J=8.42 Hz), 6.82 (1H, d J=7.60 Hz),7.19-7.34 (3H, m), 7.46 (1H, s), 7.66-7.76 (2H, m), 8.51 (1H, d J=4.04Hz), 10.29 (1H, s) ESI-MS(m/z): 478(M+Na)⁺, 459(M+1)⁺

[1919] Preparation 189

[1920] A mixture of tert-butyl5-{[(2-chloro-6-methyl-3-pyridinyl)carbonyl]amino}-1-indolinecarboxylate(1.2 g) and sodium isopropoxide (1.02 g) in tetrahydrofuran (15 ml) wasrefluxed under stirring for 10 hours. The reaction mixture wasevaporated in vacuo and the residue was dissolved in a mixture of ethylacetate and water, and the organic layer was washed with brine and driedover magnesium sulfate. The solvent was evaporated in vacuo and theresidue was chromatographed on silica gel eluting with ethylacetate:n-hexane (7:3 v/v). The eluted fractions containing the desiredproduct were collected and evaporated in vacuo to give tert-butyl5-{[(2-isopropoxy-6-methyl-3-pyridinyl)carbonyl]amino}-1-indolinecarboxylate(770 mg).

[1921]¹H-NMR(DMSO-d₆): δ 1.35 (9H, s), 1.41 (6H, d J=6.24 Hz), 2.18 (3H,s), 3.07 (2H, m), 3.91 (2H, m), 5.32-5.46 (1H, m), 6.87 (1H, s), 6.99(1H, d J=7.60 Hz), 7.32-7.41 (1H, m), 7.61 (1H, s), 8.07 (1H, d J=7.60Hz), 9.96 (1H, s)

[1922] Preparation 190

[1923] The following compound was obtained in substantially the samemanner as in Preparation 41.

[1924] N-(2,3-Dihydro-1H-indol-5-yl)-2-isopropoxy-6-methylnicotinamide

[1925]¹H-NMR(DMSO-d₆): δ 1.42 (6H, d J=6.26 Hz), 2.44 (3H, s), 2.92 (2H,t J=8.28 Hz), 3.41-3.45 (2H, m), 5.38-5.50 (2H, m), 6.48 (1H, d J=8.22Hz), 6.98 (1H, d J=7.60 Hz), 7.20 (1H, dd J=1.94 Hz, 8.22 Hz), 7.41 (1H,d J=1.94 Hz), 8.10 (1H, d J=7.60 Hz), 9.76 (1H, s)

EXAMPLE 365

[1926] The following compound was obtained in substantially the samemanner as in Example 26.

[1927]2-Isopropoxy-6-methyl-N-[1-(2-pyridinylacetyl)-2,3-dihydro-1H-indol-5-yl]nicotinamide

[1928]¹H-NMR(DMSO-d₆): δ 1.41 (6H, d J=6.14 Hz), 2.45 (3H, s), 3.18 (2H,t J=8.26 Hz), 4.01 (2H, s), 4.23 (2H, t J=8.26 Hz), 5.40-5.46 (1H, m),6.99 (1H, d J=7.68 Hz), 7.20-7.42 (3H, m), 7.67-7.77 (2H, m), 8.00 (1H,d J=8.70 Hz), 8.07 (1H, d J=7.62 Hz), 8.48-8.51 (1H, m), 10.00 (1H, s)ESI-MS(m/z): 453(M+Na)⁺, 431(M+1)⁺

[1929] Preparation 191

[1930] The following compound was obtained in substantially the samemanner as in Example 349.

[1931] tert-Butyl4-[4-({[6-methyl-2-(4-methyl-1-piperidinyl)-3-pyridinyl]carbonyl}amino)phenyl]-1-piperazinecarboxylate

[1932]¹H-NMR(DMSO-d₆): δ 0.90 (3H, d J=6.12 Hz), 1.17-1.21 (2H, m),1.42-1.50 (1H, m), 1.63-1.64 (2H, m), 2.39 (3H, s), 2.77-2.83 (2H, m),3.03-3.06 (4H, m), 3.44-3.45 (4H, m), 3.63-3.66 (2H, m), 6.82 (1H, dJ=7.60 Hz), 6.95 (2H, d J=9.00 Hz), 7.58 (2H, d J=9.00 Hz), 7.74 (1H, dJ=7.60 Hz), 10.39 (1H, s) ESI-MS(m/z): 495(M+Na)⁺, 473(M+1)⁺

[1933] Preparation 192

[1934] The following compound was obtained in substantially the samemanner as in Preparation 41.

[1935]6-Methyl-2-(4-methyl-1-piperidinyl)-N-[4-(1-piperazinyl)phenyl]nicotinamide

[1936]¹H-NMR(DMSO-d₆): δ 0.90 (3H, d J=6.14 Hz), 1.17-1.22 (2H, m),1.40-1.53 (1H, m), 1.61-1.64 (2H, m), 2.39 (3H, s), 2.77-2.83 (2H, m),2.91-2.94 (4H, m), 3.05-3.08 (4H, m), 3.58-3.66 (2H, m), 6.82 (1H, dJ=7.64 Hz), 6.93 (2H, d J=9.08 Hz), 7.58 (1H, d J=9.08 Hz), 7.75 (1H, dJ=7.64 Hz), 10.39 (1H, s)

EXAMPLE 366

[1937] A mixture of6-methyl-2-(4-methyl-1-piperidinyl)-N-[4-(1-piperazinyl)phenyl]nicotinamide(512 mg), pyrrole-2-carboxaldehyde (148 mg) and sodiumtriacetoxyborohydride (827 mg) in chloroform (20 ml) was stirred atambient temperature for 15 hours. A water (10 ml) was added to areaction mixture and adjusted to PH 8.5 with 10% potassium carbonatesolution and stirred at ambient temperature for 30 minutes. The organiclayer was washed with brine and dried over magnesium sulfate. Thesolvent was evaporated in vacuo and the residue was chromatographed onsilica gel eluting with ethyl acetate:n-hexane (6:4 v/v). The elutedfractions containing the desired product were collected and the solventwas evaporated in vacuo and the residue was recrystallized from amixture of diisopropyl ether and n-hexane to give6-methyl-2-(4-methyl-1-piperidinyl)-N-{4-[4-(1H-pyrrol-2-ylmethyl)-1-piperazinyl]phenyl}nicotinamide(260 mg).

[1938]¹H-NMR(DMSO-d₆): δ 0.90 (3H, d J=6.20 Hz), 1.11-1.29 (2H, m),1.46-1.66 (3H, m), 2.39 (3H, s), 2.48-2.51 (4H, m), 2.74-2.86 (2H, m),3.34-3.44 (4H, m), 3.77 (2H, s), 4.01-4.05 (2H, m), 5.88-5.95 (2H, m),6.63-6.66 (1H, m), 6.82 (1H, d J=7.56 Hz), 6.91 (2H, d J=8.94 Hz), 7.56(2H, d J=8.94 Hz), 7.75 (1H, d J=7.56 Hz), 10.38 (1H, s)

EXAMPLE 367

[1939] The following compound was obtained in substantially the samemanner as in Example 366.

[1940]6-Methyl-2-(4-methyl-1-piperidinyl)-N-{4-[4-(2-thienylmethyl)-1-piperazinyl]phenyl}nicotinamide

[1941]¹H-NMR(DMSO-d₆): δ 0.90 (3H, d J=6.14 Hz), 1.17-1.29 (2H, m),1.41-1.66 (3H, m), 2.39 (3H, s), 2.50-2.57 (4H, m), 2.74-2.86 (2H, m),3.07-3.12 (4H, m), 3.73 (2H, s), 3.60-3.67 (2H, m), 6.82 (1H, d J=7.68Hz), 6.89-6.99 (4H, m), 7.43-7.46 (1H, m), 7.57 (2H, d J=8.94 Hz), 7.75(1H, d J=7.58 Hz), 10.39 (1H, s) ESI-MS(m/z): 512(M+Na)⁺, 490(M+1)⁺

EXAMPLE 368

[1942] The following compound was obtained in substantially the samemanner as in Example 366.

[1943]N-{4-[4-(2-Furylmethyl)-1-piperazinyl]phenyl}-6-methyl-2-(4-methyl-1-piperidinyl)nicotinamide

[1944]¹H-NMR(DMSO-d₆): δ 0.90 (3H, d J=6.16 Hz), 1.11-1.29 (2H, m),1.46-1.66 (3H, m), 2.39 (3H, s), 2.49-2.54 (4H, m), 2.74-2.86 (2H, m),3.06-3.11 (4H, m), 3.54 (2H, s), 3.60-3.67 (2H, m), 6.31 (1H, d J=3.18Hz), 6.41-6.43 (1H, m), 6.82 (1H, d J=7.56 Hz), 6.91 (2H, d J=9.00 hz),7.56 (2H, d J=9.00 Hz), 7.60-7.61 (1H, m), 7.75 (1H, d J=7.56 Hz), 10.38(1H, s) ESI-MS(m/z): 496(M+Na)⁺, 474(M+1)⁺

[1945] Preparation 193

[1946] The following compound was obtained in substantially the samemanner as in Example 349.

[1947] tert-Butyl4-{4-[(2-isopropoxy-4-methylbenzoyl)amino]phenyl}-1-piperazinecarboxylate

[1948]¹H-NMR(DMSO-d₆): δ 1.38 (6H, d J=6.00 Hz), 1.42 (9H, s), 2.36 (3H,s), 3.03-3.07 (4H, m), 3.45-3.49 (4H, m), 4.75-4.87 (1H, m), 6.86-7.03(3H, m), 7.03 (1H, s), 7.56 (2H, d J=8.90 Hz), 7.74 (1H, d J=7.80 Hz),9.96 (1H, s)

[1949] Preparation 194

[1950] The following compound was obtained in substantially the samemanner as in Preparation 41.

[1951] 2-Isopropoxy-4-methyl-N-[4-(1-piperazinyl)phenyl]benzamide

[1952]¹H-NMR(DMSO-d₆): δ 1.39 (6H, d J=6.00 Hz), 2.36 (3H, s), 3.25-3.30(8H, m), 4.75-4.87 (1H, m), 6.88 (1H, d J=7.70 Hz), 6.97-7.04 (3H, m),7.59 (2H, d J=8.94 Hz), 7.72 (1H, d J=7.88 Hz), 8.76 (1H, m), 9.98 (1H,s)

EXAMPLE 369

[1953] The following compound was obtained in substantially the samemanner as in Example 366.

[1954]2-Isopropoxy-4-methyl-N-{4-[4-(1H-pyrrol-2-ylmethyl)-1-piperazinyl]phenyl}benzamide

[1955]¹H-NMR(DMSO-d₆): δ 1.38 (6H, d J=6.02 Hz), 2.35 (3H, s), 2.49-2.50(4H, m), 3.06-3.08 (4H, m), 3.47 (2H, s), 4.75-4.87 (1H, m), 5.90-5.96(2H, m), 6.63-6.66 (1H, m), 6.86-6.94 (2H, m), 7.03 (1H, s), 7.54 (2H, dJ=8.92 Hz), 7.73 (1H, d J=7.90 hz), 9.94 (1H, s), 10.70 (1H, s)ESI-MS(m/z): 455(M+Na)⁺, 433(M+1)⁺

EXAMPLE 370

[1956] The following compound was obtained in substantially the samemanner as in Example 366.

[1957]N-{4-[4-(3-Cyanobenzyl)-1-piperazinyl]phenyl}-2-isopropoxy-4-methylbenzamide

[1958]¹H-NMR(DMSO-d₆): δ 1.39 (6H, d J=6.00 Hz), 2.36 (3H, s), 2.50-2.52(4H, m), 3.08-3.11 (4H, m), 3.59 (2H, s), 4.75-4.87 (1H, m), 6.86-6.94(3H, m), 7.03 (1H, s), 7.52-7.60 (3H, m), 7.68-7.77 (4H, m), 9.95 (1H,s)

[1959] Preparation 195

[1960] A solution of 2-chloro-6-methylnicotinoyl chloride (1.91 g) intetrahydrofuran (10 ml) was added to a mixture of6-amino-2-[2-(2-pyridinyl)ethyl]-1-isoindolinone (2.58 g) andtriethylamine (4.06 g) in tetrahydrofuran (50 ml) at ambient temperaturewith stirring. The mixture was stirred at ambient temperature for 5hours. The resultant mixture was poured into a mixture of ethyl acetateand water and the organic layer was washed with 5% potassium carbonatesolution and brine and dried over magnesium sulfate. The solvent wasevaporated in vacuo and the residue was chromatographed on silica geleluting with chloroform: methanol (95:5 v/v). The eluted fractionscontaining the desired product were collected and the solvent wasconcentrated in vacuo and the precipitate was collected by filtration togive2-chloro-6-methyl-N-{3-oxo-2-[2-(2-pyridinyl)ethyl]-2,3-dihydro-1H-isoindol-5-yl}nicotinamide(2.86 g).

[1961]¹H-NMR(DMSO-d₆): δ 2.53 (3H, s), 3.09 (2H, t J=7.28 Hz), 3.91 (2H,t J=7.28 Hz), 4.40 (2H, s), 7.21-7.25 (1H, m), 7.30 (1H, d J=7.86 Hz),7.43 (1H, d J=7.76 Hz), 7.55 (1H, d J=8.24 Hz), 7.65-7.80 (2H, m), 7.99(1H, d J=7.76 Hz), 8.08 (1H, d J=1.70 Hz), 8.47-8.50 (1H, m), 10.76 (1H,s)

EXAMPLE 373

[1962] The following compound was obtained in substantially the samemanner as in Example 364.

[1963]6-Methyl-2-(4-methyl-1-piperidinyl)-N-{3-oxo-2-[2-(2-pyridinyl)ethyl]-2,3-dihydro-1H-isoindol-5-yl}nicotinamide

[1964]¹H-NMR(DMSO-d₆): δ 0.87 (3H, d J=6.20 Hz), 1.14-1.25 (2H, m),1.47-1.64 (3H, m), 2.40 (3H, s), 2.75-2.87 (2H, m), 3.08 (2H, t J=7.34Hz), 3.65-3.71 (2H, m), 3.90 (2H, t J=7.34 Hz), 4.39 (2H, s), 6.82 (1H,d J=7.66 Hz), 7.21-7.25 (1H, m), 7.31 (1H, d J=7.88 Hz), 7.53 (1H, dJ=8.20 Hz), 7.66-7.82 (3H, m), 8.13 (1H, d J=1.54 Hz), 8.48-8.50 (1H,m), 10.56 (1H, s) negative ESI-MS(m/z): 468 (M−1)⁻

[1965] Preparation 196

[1966] The mixture of 2-fluoro-3-(trifluoromethyl)benzonitrile (2.8 g)and 2 moL/L tetrahydrofuran solution of dimethylamine (22.2 ml) washeated at 80° C. in sealed tube for 7 hours. To the reaction mixture wasadded a mixture of ethyl acetate and water. The separated organic layerwas washed with water, dried over magnesium sulfate and evaporated invacuo to give 2-(dimethylamino)-3-(trifluoromethyl)benzonitrile (3.04g).

[1967]¹H-NMR(DMSO-d₆): δ 2.88(6H, s), 7.52-7.58(1H, m), 8.02(1H, dd,J=1.3 Hz, 8.0 Hz), 8.11(1H, dd, J=1.3 Hz, 7.8 Hz)

[1968] Preparation 197

[1969] The mixture of 2-(dimethylamino)-3-(trifluoromethyl)benzonitrile(3.0 g) and sodium hydroxide (1.1 g) in ethylene glycol (12 mL) wasstirred at 180° C. for 8 hours. After the mixture was added a water (22mL) at 80° C. and the mixture was stirred at same temperature for 1hour. To the mixture was added saturated aqueous sodium chloride andadjusted to pH 4 with 6N hydrochloric acid. The mixture was extractedwith a mixture of ethyl acetate and tetrahydrofuran. The extract layerwas dried over magnesium sulfate and evaporated in vacuo. The residuewas purified by column chromatography on silica gel using a mixture ofethyl acetate and isopropyl ether (1:1 v/v) as an eluant. The elutedfractions containing the desired product were collected and evaporatedin vacuo to give 2-(dimethylamino)-3-(trifluoromethyl)benzoic acid (1.01g).

[1970]¹H-NMR(DMSO-d₆): δ 2.76(6H, s), 7.42(1H, t, J=7.7 Hz),7.75-7.92(2H, m), 13.55(1H, s) (+)ESI-MS(m/z): 234(M+H)⁺, 256(M+Na)⁺

EXAMPLE 374

[1971] 1-[3-(Dimethylamino)propyl]-3-ethylcarbodiimide (0.19 g) wasadded to the solution of 1-(2-pyridinylacetyl)-5-indolinamine (0.25 g),2-(dimethylamino)-3-(trifluoromethyl)benzoic acid (0.28 g),1-hydroxybenzotriazole (0.16 g) and 4-dimethylaminopyridine (6 mg) indimethylformamide (5 ml) under ice-cooling and the mixture was stirredat ambient temperature for 18 hours. The reaction mixture was pouredinto a mixture of ethyl acetate and water. The separated organic layerwas washed with water, dried over magnesium sulfate and evaporated invacuo. The residue was triturated with a mixture of ethyl acetate andisopropyl ether to give2-(dimethylamino)-N-[1-(2-pyridinylacetyl)-2,3-dihydro-1H-indol-5-yl]-3-(trifluoromethyl)benzamide(0.19 g).

[1972]¹H-NMR(DMSO-d₆): δ 2.74(6H, s), 3.18(2H, t, J=8.3 Hz), 4.01(2H,s), 4.22(2H, t, J=8.3 Hz), 7.28(1H, dd, J=5.2 Hz,6.8 Hz), 7.33-7.50(3H,m), 7.63-7.86(4H, m), 8.01(1H, d, J=8.7 Hz), 8.48-8.54(1H, m), 10.46(1H,s) (+) ESI-MS (m/z): 469 (M+H)⁺, 491 (M+Na)⁺

EXAMPLE 375

[1973] The following compound was obtained in substantially the samemanner as in Example 374.

[1974]2-(Dimethylamino)-3-methyl-N-[1-(2-pyridinylacetyl)-2,3-dihydro-1H-indol-5-yl]benzamide

[1975]¹H-NMR(DMSO-d₆): δ 2.31(3H, s), 2.75(6H, s), 3.17(2H, t, J=8.3Hz), 4.01(2H, s), 4.22(2H, t, J=8.3 Hz), 7.08(1H, t, J=7.5 Hz),7.23-7.48(5H, m), 7.69-7.83(2H, m), 7.98(1H, dd, J=8.7 Hz),8.47-8.54(1H, m), 10.78(1H, s) (+)ESI-MS(m/z): 415(M+H)⁺, 437(M+Na)⁺

EXAMPLE 376

[1976] The following compound was obtained in substantially the samemanner as in Example 374.

[1977]2-(Dimethylamino)-N-[1-(2-pyridinylacetyl)-2,3-dihydro-1H-indol-5-yl]-4-(trifluoromethyl)benzamide

[1978]¹H-NMR(DMSO-d₆): δ 2.85(6H, s), 3.17(2H, t, J=8.3 Hz), 4.01(2H,s), 4.22(2H, t, J=8.3 Hz), 7.20-7.47(5H, m), 7.62(1H, d, J=8.0 Hz),7.69(1H, s), 7.77(1H, dt, J=1.8 Hz,7.6 Hz), 7.99(1H, d, J=8.7 Hz),8.47-8.53(1H, m), 10.57(1H, s) (+)ESI-MS(m/z): 469(M+H)⁺, 491(M+Na)⁺

EXAMPLE 377

[1979] The following compound was obtained in substantially the samemanner as in Example 374.

[1980]4-Chloro-2-(dimethylamino)-N-[1-(2-pyridinylacetyl)-2,3-dihydro-1H-indol-5-yl]benzamide

[1981]¹H-NMR(DMSO-d₆): δ 2.80(6H, s), 3.16(2H, t, J=8.3 Hz), 4.01(2H,s), 4.22(2H, t, J=8.3 Hz), 7.02(1H, dd, J=1.8 Hz,8.2 Hz), 7.10(1H, d,J=1.8 Hz), 7.27(1H, dd, J=5.4 Hz, 7.1 Hz), 7.33-7.47(2H, m), 7.53(1H, d,J=8.2 Hz), 7.69(1H, s), 7.71-7.82(1H, m), 7.99(1H, d, J=8.7 Hz),8.48-8.54(1H, m), 10.71(1H, s) (+)ESI-MS(m/z): 435(M+H)⁺, 457(M+Na)⁺

EXAMPLE 378

[1982] The following compound was obtained in substantially the samemanner as in Example 374.

[1983]2-(Dimethylamino)-4-fluoro-N-[1-(2-pyridinylacetyl)-2,3-dihydro-1H-indol-5-yl]benzamide

[1984]¹H-NMR(DMSO-d₆): δ 2.79(6H, s), 3.17(2H, t, J=8.3 Hz), 4.01(2H,s), 4.22(2H, t, J=8.3 Hz), 6.73-6.85(1H, m), 6.90(1H, dd, J=2.4 Hz, 12.1Hz), 7.24-7.32(1H, m), 7.33-7.46(2H, m), 7.52-7.62(1H, m), 7.69(1H, s),7.72-7.82(1H, m), 7.98(1H, d, J=8.6 Hz), 8.48-8.53(1H, m), 10.68(1H, s)(+) ESI-MS (m/z): 419 (M+H)⁺, 441 (M+Na)⁺

EXAMPLE 379

[1985] The following compound was obtained in substantially the samemanner as in Example 374.

[1986]2-(Dimethylamino)-4-ethyl-N-[1-(2-pyridinylacetyl)-2,3-dihydro-1H-indol-5-yl]benzamide

[1987]¹H-NMR(DMSO-d₆): δ 1.20(3H, t, J=7.5 Hz), 2.63(2H, q, J=7.5 Hz),2.76(6H, s), 3.17(2H, t, J=8.3 Hz), 4.01(2H, s), 4.22(2H, t, J=8.3 Hz),6.94-7.01(1H, m), 7.10(1H, s), 7.23-7.32(1H, m), 7.34-7.47(2H, m),7.63-7.82(3H, m), 8.00(1H, d, J=8.6 Hz), 8.48-8.53(1H, m), 11.43(1H, s)(+)ESI-MS(m/z): 429 (M+H)⁺, 451 (M+Na)⁺

EXAMPLE 380

[1988] The following compound was obtained in substantially the samemanner as in Example 374.

[1989]2-(Dimethylamino)-4-isopropyl-N-[1-(2-pyridinylacetyl)-2,3-dihydro-1H-indol-5-yl]benzamide

[1990]¹H-NMR(DMSO-d₆): δ 1.22(6H, d, J=6.8 Hz), 2.77(6H, s),2.83-3.01(1H, m), 3.17(2H, t, J=8.3 Hz), 4.01(2H, s), 4.22(2H, t, J=8.3Hz), 7.01(1H, d, J=8.1 Hz), 7.10(1H, s), 7.23-7.33(1H, m), 7.33-7.48(2H,m), 7.63-7.82(3H, m), 7.99(1H, d, J=8.6 Hz), 8.48-8.53(1H, m), 11.36(1H,s) (+)ESI-MS(m/z): 443(M+H)⁺, 465(M+Na)⁺

EXAMPLE 381

[1991] The following compound was obtained in substantially the samemanner as in Example 374.

[1992]4-tert-Butyl-2-(dimethylamino)-N-[1-(2-pyridinylacetyl)-2,3-dihydro-1H-indol-5-yl]benzamide

[1993]¹H-NMR(DMSO-d₆): δ 1.31(9H, s), 2.78(6H, s), 3.17(2H, t, J=8.3Hz), 4.01(2H, s), 4.22(2H, t, J=8.3 Hz), 7.15(1H, dd, J=1.6 Hz, 8.2 Hz),7.20-7.33(2H, m), 7.34-7.47(2H, m), 7.64-7.83(3H, m), 7.99(1H, d, J=8.6Hz), 8.48-8.54(1H, m), 11.41(1H, s) (+)ESI-MS(m/z): 457 (M+H)⁺, 479(M+Na)⁺

EXAMPLE 382

[1994] The following compound was obtained in substantially the samemanner as in Example 374.

[1995]2-(Dimethylamino)-4-methoxy-N-[1-(2-pyridinylacetyl)-2,3-dihydro-1H-indol-5-yl]benzamide

[1996]¹H-NMR(DMSO-d₆): δ 2.76(6H, s), 3.17(2H, t, J=8.3 Hz), 3.81(3H,s), 4.01(2H, s), 4.23(2H, t, J=8.3 Hz), 6.68-6.78(2H, m), 7.24-7.45(3H,m), 7.69-7.82(3H, m), 7.98(1H, d, J=8.5 Hz), 8.48-8.52(1H, m), 11.41(1H,s) (+)ESI-MS(m/z): 431(M+H)⁺, 453(M+Na)⁺

EXAMPLE 383

[1997] The following compound was obtained in substantially the samemanner as in Example 374.

[1998]4-Acetyl-2-(dimethylamino)-N-[1-(2-pyridinylacetyl)-2,3-dihydro-1H-indol-5-yl]benzamide

[1999]¹H-NMR(DMSO-d₆): δ 2.61(3H, s), 2.83(6H, s), 3.17(2H, t, J=8.4Hz), 4.01(2H, s), 4.23(2H, t, J=8.4 Hz), 7.24-7.32(1H, m), 7.37(1H, d,J=7.7 Hz), 7.39-7.48(1H, m), 7.56-7.82(5H, m), 8.00(1H, d, J=8.7 Hz),8.48-8.53(1H, m), 10.86(1H, s) (+)ESI-MS(m/z): 443(M+H)⁺, 465(M+Na)⁺

EXAMPLE 384

[2000] The following compound was obtained in substantially the samemanner as in Example 374.

[2001]2-(Dimethylamino)-5-methyl-N-[1-(2-pyridinylacetyl)-2,3-dihydro-1H-indol-5-yl]benzamide

[2002]¹H-NMR(DMSO-d₆): δ 2.30(3H, s), 2.73(6H, s), 3.18(2H, t, J=8.4Hz), 4.01(2H, s), 4.22(2H, t, J=8.4 Hz), 7.21(1H, d, J=8.2 Hz),7.26-7.32(2H, m), 7.37(1H, d, J=7.8 Hz), 7.43(1H, d, J=8.6 Hz), 7.60(1H,s), 7.71(1H, s), 7.74-7.80(1H, m), 8.00(1H, d, J=8.6 Hz), 8.49-8.53(1H,m), 11.71(1H, s) (+)ESI-MS(m/z): 415(M+H)⁺, 437(M+Na)⁺

EXAMPLE 385

[2003] The following compound was obtained in substantially the samemanner as in Example 374.

[2004]5-Chloro-2-(dimethylamino)-N-[1-(2-pyridinylacetyl)-2,3-dihydro-1H-indol-5-yl]benzamide

[2005]¹H-NMR(DMSO-d₆): δ 2.77(6H, s), 3.17(2H, t, J=8.3 Hz), 4.01(2H,s), 4.22(2H, t, J=8.3 Hz), 7.17(1H, d, J=8.8 Hz), 7.23-7.32(1H, m),7.34-7.49(3H, m), 7.56(1H, d, J=2.5 Hz), 7.70(1H, s), 7.72-7.82(1H, m),8.00(1H, d, J=8.6 Hz), 8.47-8.53(1H, m), 11.00(1H, s) (+)ESI-MS(m/z):435(M+H)⁺, 457(M+Na)⁺

EXAMPLE 386

[2006] The following compound was obtained in substantially the samemanner as in Example 374.

[2007]2-(Dimethylamino)-4,5-dimethoxy-N-[1-(2-pyridinylacetyl)-2,3-dihydro-1H-indol-5-yl]benzamide

[2008]¹H-NMR(DMSO-d₆): δ 2.75(6H, s), 3.18(2H, t, J=8.4 Hz), 3.79(3H,s), 3.86(3H, s), 4.01(2H, s), 4.23(2H, t, J=8.4 Hz), 7.05(1H, s),7.24-7.33(1H, m), 7.33-7.47(2H, m), 7.56(1H, s), 7.68-7.83(2H, m),8.00(1H, d, J=8.6 Hz), 8.47-8.53(1H, m), 12.71(1H, s) (+)ESI-MS(m/z):461(M+H)⁺, 483(M+Na)⁺

EXAMPLE 387

[2009] The following compound was obtained in substantially the samemanner as in Example 374.

[2010]2-(Diethylamino)-4-methyl-N-[1-(2-pyridinylacetyl)-2,3-dihydro-1H-indol-5-yl]benzamide¹H-NMR(DMSO-d₆): δ 0.96(6H, t, J=7.1 Hz), 2.37(3H, s), 3.02-3.27(6H, m),4.01(2H, s), 4.23(2H, t, J=8.3 Hz), 7.15(1H, d, J=8.1 Hz), 7.22-7.47(4H,m), 7.67-7.83(2H, m), 7.97-8.07(2H, m), 8.47-8.55(1H, m), 13.13(1H, s)(+) ESI-MS (m/z): 443 (M+H)⁺, 465 (M+Na)⁺

EXAMPLE 388

[2011] The following compound was obtained in substantially the samemanner as in Example 374.

[2012] tert-Butyl[5-methyl-2-({[1-(2-pyridinylacetyl)-2,3-dihydro-1H-indol-5-yl]amino}carbonyl)phenyl]carbamate

[2013]¹H-NMR(DMSO-d₆): δ 1.46(9H, s), 2.35(3H, s), 3.18(2H, t, J=8.3Hz), 4.02(2H, s), 4.23(2H, t, J=8.3 Hz), 6.96(1H, d, J=7.3 Hz),7.24-7.32(1H, m), 7.34-7.45(2H, m), 7.65(1H, s), 7.71-7.82(2H, m),7.97-8.06(2H, m), 8.48-8.54(1H, m), 10.26(1H, s), 10.30(1H, s) (+)ESI-MS (m/z): 487 (M+H)⁺, 509 (M+Na)⁺

EXAMPLE 389

[2014] The mixture of tert-butyl5-methyl-2-({[1-(2-pyridinylacetyl)-2,3-dihydro-1H-indol-5-yl]amino}carbonyl)phenylcarbamate(1.5 g) and trifluoroacetic acid (1.9 mL) in dichloromethane (3.0 mL)was stirred for 20 hours at ambient temperature. The reaction mixturewas poured into a mixture of ethyl acetate and water and the mixture wasadjusted to pH 9 with potassium carbonate. The isolated precipitate wascollected by filtration to give2-amino-4-methyl-N-[1-(2-pyridinylacetyl)-2,3-dihydro-1H-indol-5-yl]benzamide(1.14 g).

[2015]¹H-NMR(DMSO-d₆): δ 2.20(3H, s), 3.15(2H, t, J=8.3 Hz), 4.00(2H,s), 4.22(2H, t, J=8.3 Hz), 4.27-4.46(3H, m), 6.54(1H, s), 6.23-6.33(1H,m), 6.33-6.47(2H, m), 6.54(1H, d, J=8.0 Hz), 7.65(1H, s), 7.71-7.82(1H,m), 7.97(1H, d, J=8.7 Hz), 8.47-8.54(1H, m), 9.83(1H, s) (−)ESI-MS(m/z):385(M−H)⁻

EXAMPLE 390

[2016] The following compound was obtained in substantially the samemanner as in Example 374.

[2017]4-Methoxy-2-(4-methyl-1-piperidinyl)-N-[1-(2-pyridinylacetyl)-2,3-dihydro-1H-indol-5-yl]benzamide

[2018]¹H-NMR(DMSO-d₆): δ 0.95(3H, d, J=5.9 Hz), 1.20-1.63(3H, m),1.65-1.82(2H, m), 2.70-2.86(2H, m), 3.03-3.25(4H, m), 3.82(3H, s),4.01(2H, s), 4.23(2H, t, J=8.3 Hz), 6.77-6.86(2H, m), 7.24-7.33(1H, m),7.33-7.44(2H, m), 7.72-7.84(2H, m), 7.88(1H, d, J=8.7 Hz), 8.02(1H, d,J=8.7 Hz), 8.47-8.55(1H, m), 11.76(1H, s) (+)ESI-MS(m/z): 485(M+H)⁺, 507(M+Na)⁺

EXAMPLE 391

[2019] The following compound was obtained in substantially the samemanner as in Example 374.

[2020]1-Methyl-N-[1-(2-pyridinylacetyl)-2,3-dihydro-1H-indol-5-yl]-1,2,3,4-tetrahydro-8-quinolinecarboxamide

[2021]¹H-NMR(DMSO-d₆): δ 1.18-1.89(2H, m), 2.73(2H, t, J=6.3 Hz),2.76(3H, s), 3.13-3.22(4H, m), 4.00(2H, s), 4.21(2H, t, J=8.4 Hz),6.76(1H, t, J=7.5 Hz), 7.06(1H, d, J=7.5 Hz), 7.25-7.31(2H, m), 7.37(1H,d, J=7.5 Hz), 7.42(1H, d, J=8.7 Hz), 7.69(1H, s), 7.74-7.80(1H, m),7.98(1H, d, J=8.7 Hz), 8.49-8.53(1H, m), 10.39(1H, s) (+) ESI-MS (m/z):427 (M+H)⁺, 449 (M+Na)⁺

EXAMPLE 392

[2022] The following compound was obtained in substantially the samemanner as in Example 374.

[2023]1-Ethyl-N-[1-(2-pyridinylacetyl)-2,3-dihydro-1H-indol-5-yl]-1,2,3,4-tetrahydro-8-quinolinecarboxamide

[2024]¹H-NMR(DMSO-d₆): δ 0.97(3H, t, J=7.0 Hz), 1.71-1.88(2H, m),2.76(2H, t, J=6.2 Hz), 3.01(2H, q, J=7.0 Hz), 3.08-3.24(4H, m), 4.00(2H,s), 4.21(2H, t, J=8.4 Hz), 6.83(1H, t, J=7.5 Hz), 7.03-7.13(1H, m),7.22-7.33(2H, m), 7.36(1H, d, J=7.8 Hz), 7.43(1H, dd, J=2.0 Hz, 8.5 Hz),7.69-7.83(2H, m), 7.97(1H, d, J=8.7 Hz), 8.46-8.54(1H, m), 10.40(1H, s)(+)ESI-MS(m/z): 441(M+H)⁺, 463(M+Na)⁺

EXAMPLE 393

[2025] The following compound was obtained in substantially the samemanner as in Example 374.

[2026]5-Chloro-1-methyl-N-[1-(2-pyridinylacetyl)-2,3-dihydro-1H-indol-5-yl]-1,2,3,4-tetrahydro-8-quinolinecarboxamide

[2027]¹H-NMR(DMSO-d₆): δ 1.79-1.95(2H, m), 2.74(2H, t, J=6.3 Hz),2.78(3H, s), 3.09-3.23(4H, m), 4.00(2H, s), 4.22(2H, t, J=8.3 Hz),6.89(1H, d, J=8.2 Hz), 7.22-7.33(2H, m), 7.33-7.45(2H, m), 7.67(1H, s),7.76(1H, dt, J=1.8Hz, 7.7 Hz), 7.98(1H, d, J=8.7 Hz), 8.47-8.53(1H, m),10.29(1H, s) (+)ESI-MS(m/z): 461(M+H)⁺, 483(M+Na)⁺

[2028] Preparation 198

[2029] A mixture of methyl 3-amino-4-methyl-2-thiophenecarboxylate (5.0g), sodium hydrogencarbonate (14.7 g) and dimethyl sulfate (8.3 mL) in2-butanone (50 mL) was heated under reflux for 17 hours. The solvent wasremoved by concentration. The residue was diluted with water andextracted with ethyl acetate. The extract layer was washed with water,dried over magnesium sulfate and evaporated in vacuo to give methyl3-(dimethylamino)-4-methyl-2-thiophenecarboxylate (5.65 g).

[2030]¹H-NMR(DMSO-d₆): δ 2.13(3H, s), 2.83(6H, s), 3.73(3H, s), 7.36(1H,s)

[2031] Preparation 199

[2032] A mixture of methyl3-(dimethylamino)-4-methyl-2-thiophenecarboxylate (5.6 g) and lithiumhydroxide monohydrate (2.4 g) in a mixture of methanol (56 ml) and water(12 mL) was stirred for 6 days at ambient temperature. To the reactionmixture was added conc. hydrochloric acid (4.7 mL) and the mixture wasevaporated in vacuo. The residue was purified by column chromatographyon silica gel using a mixture of chloroform and methanol (19:1 v/v) asan eluant. The eluted fractions containing the desired product werecollected and evaporated in vacuo to give3-(dimethylamino)-4-methyl-2-thiophenecarboxylic acid (0.55 g).

[2033]¹H-NMR(DMSO-d₆): δ 2.24(3H, d, J=0.8 Hz), 2.84(6H, s), 7.43(1H, d,J=0.8 Hz), 14.50(1H, s) (−)ESI-MS(m/z): 184(M−H)⁻

EXAMPLE 394

[2034] The following compound was obtained in substantially the samemanner as in Example 374.

[2035]3-(Dimethylamino)-4-methyl-N-[1-(2-pyridinylacetyl)-2,3-dihydro-1H-indol-5-yl]-2-thiophenecarboxamide

[2036]¹H-NMR(DMSO-d₆): δ 2.31(3H, s), 2.87(6H, s), 3.18(2H, t, J=8.3Hz), 4.01(2H, s), 4.23(2H, t, J=8.3 Hz), 7.23-7.33(1H, m), 7.34-7.45(3H,m), 7.65(1H, s), 7.77(1H, dt, J=1.7 Hz, 7.6 Hz), 8.02(1H, d, J=8.6 Hz),8.48-8.54(1H, m), 11.90(1H, s) (+)ESI-MS(m/z): 421(M+H)⁺, 443 (M+Na)⁺

EXAMPLE 395

[2037] The following compound was obtained in substantially the samemanner as in Example 374.

[2038]2-Isopropyl-4-methyl-N-[1-(2-pyridinylacetyl)-2,3-dihydro-1H-indol-5-yl]benzamide

[2039]¹H-NMR(DMSO-d₆): δ 1.20(6H, d, J=6.9 Hz), 2.34(3H, s),3.07-3.36(3H, m), 4.00(2H, s), 4.21(2H, t, J=8.4 Hz), 7.07(1H, d, J=8.1Hz), 7.20-7.48(5H, m), 7.69-7.82(2H, m), 7.97(1H, d, J=8.7 Hz),8.47-8.54(1H, m), 10.21(1H, s) (+)ESI-MS(m/z): 414(M+H)⁺, 436(M+Na)⁺

EXAMPLE 396

[2040] The following compound was obtained in substantially the samemanner as in Example 374.

[2041]2-Isopropenyl-4-methyl-N-[1-(2-pyridinylacetyl)-2,3-dihydro-1H-indol-5-yl]benzamide

[2042]¹H-NMR(DMSO-d₆): δ 2.03(3H, s), 2.34(3H, s), 3.15(2H, t, J=8.3Hz), 4.00(2H, s), 4.21(2H, t, J=8.3 Hz), 4.94(1H, s), 5.05(1H, s),7.13-7.42(6H, m), 7.64(1H, s), 7.76(1H, dt, J=1.8 Hz, 7.6 Hz), 7.96(1H,d, J=8.7 Hz), 8.47-8.54(1H, m), 10.08(1H, s) (+)ESI-MS(m/z): 412(M+H)⁺,434(M+Na)⁺

EXAMPLE 397

[2043] The following compound was obtained in substantially the samemanner as in Example 374.

[2044]2-tert-Butyl-4-methyl-N-[1-(2-pyridinylacetyl)-2,3-dihydro-1H-indol-5-yl]benzamide

[2045]¹H-NMR(DMSO-d₆): δ 1.36(9H, s), 2.33(3H, s), 3.16(2H, t, J=8.3Hz), 4.00(2H, s), 4.21(2H, t, J=8.3 Hz), 7.05-7.11(1H, m), 7.14(1H, d,J=7.6 Hz), 7.23-7.44(4H, m), 7.68(1H, s), 7.71-7.81(1H, m), 7.96(1H, d,J=8.7 Hz), 8.48-8.53(1H, m), 10.23(1H, s) (+)ESI-MS(m/z): 428(M+H)⁺,450(M+Na)⁺

EXAMPLE 398

[2046] The following compound was obtained in substantially the samemanner as in Example 374.

[2047]4-Chloro-2-cyclohexyl-N-[1-(2-pyridinylacetyl)-2,3-dihydro-1H-indol-5-yl]benzamide

[2048]¹H-NMR(DMSO-d₆): δ 1.08-1.58(5H, m), 1.58-1.94(5H, m),2.74-2.96(1H, m), 3.17(2H, t, J=8.2 Hz), 4.01(2H, s), 4.22(2H, t, J=8.2Hz), 7.20-7.51(6H, m), 7.64-7.84(2H, m), 7.99(1H, d, J=8.7 Hz),8.44-8.56(1H, m), 10.33(1H, s) (+)ESI-MS(m/z): 474(M+H)⁺, 496(M+Na)⁺

EXAMPLE 399

[2049] The following compound was obtained in substantially the samemanner as in Example 374.

[2050]2-Cyclohexyl-N-[1-(2-pyridinylacetyl)-2,3-dihydro-1H-indol-5-yl]benzamide

[2051]¹H-NMR(DMSO-d₆): δ 1.16-1.31(3H, m), 1.37-1.51(2H, m),1.62-1.87(5H, m), 2.78-2.89(1H, m), 3.17(2H, t, J=8.3 Hz), 4.01(2H, s),4.22(2H, t, J=8.3 Hz), 7.23-7.47(7H, m), 7.71(1H, s), 7.77(1H, dt, J=1.7Hz, 7.6 Hz), 7.98(1H, d, J=8.7 Hz), 8.48-8.54(1H, m), 10.28(1H, s)(+)ESI-MS(m/z): 440(M+H)⁺, 462(M+Na)⁺

EXAMPLE 400

[2052] The following compound was obtained in substantially the samemanner as in Example 374.

[2053]2-(Methylthio)-N-[1-(2-pyridinylacetyl)-2,3-dihydro-1H-indol-5-yl]benzamide

[2054]¹H-NMR(DMSO-d₆): δ 2.43(3H, s), 3.16(2H, t, J=8.3 Hz), 4.01(2H,s), 4.22(2H, t, J=8.3 Hz), 7.19-7.54(7H, m), 7.66-7.84(2H, m), 7.98(1H,d, J=8.7 Hz), 8.45-8.56(1H, m), 10.26(1H, s) (+)ESI-MS(m/z): 404(M+H)⁺,426(M+Na)⁺

EXAMPLE 401

[2055] The following compound was obtained in substantially the samemanner as in Example 374.

[2056]2-(Methylsulfonyl)-N-[1-(2-pyridinylacetyl)-2,3-dihydro-1H-indol-5-yl]benzamide

[2057]¹H-NMR(DMSO-d₆): δ 3.18(2H, t, J=8.3 Hz), 3.38(3H, s), 4.01(2H,s), 4.23(2H, t, J=8.3 Hz), 7.23-7.33(1H, m), 7.37(2H, d, J=7.9 Hz),7.66-7.89(5H, m), 7.96-8.06(2H, m), 8.48-8.54(1H, m), 10.57(1H, s)(+)ESI-MS(m/z): 436(M+H)⁺, 458(M+Na)⁺

EXAMPLE 402

[2058] The following compound was obtained in substantially the samemanner as in Example 374.

[2059]4-Methyl-2-(methylthio)-N-[1-(2-pyridinylacetyl)-2,3-dihydro-1H-indol-5-yl]benzamide

[2060]¹H-NMR(DMSO-d₆): δ 2.36(3H, s), 2.42(3H, s), 3.16(2H, t, J=8.2Hz), 4.00(2H, s), 4.21(2H, t, J=8.2 Hz), 7.05(1H, d, J=7.7 Hz), 7.21(1H,s), 7.23-7.33(1H, m), 7.33-7.48(3H, m), 7.66-7.82(2H, m), 7.98(1H, d,J=8.7 Hz), 8.47-8.54(1H, m), 10.17(1H, s) (+)ESI-MS(m/z): 418(M+H)⁺,440(M+Na)⁺

EXAMPLE 403

[2061] 1-[3-(Dimethylamino)propyl]-3-ethylcarbodiimide (0.19 g) wasadded to a solution of tert-butyl4-aminophenyl(2-(2-pyridinyl)ethyl)carbamate (0.31 g),2-isopropyl-4-methylbenzoic acid (0.21 g), 1-hydroxybenzotriazole (0.16g) and 4-dimethylaminopyridine (6 mg) in tetrahydrofuran (4 ml), and themixture was stirred at ambient temperature for 18 hours. To the reactionmixture was added a solution of 4N solution of hydrogen chloride indioxane (7.5 ml) and the mixture was stirred at same temperature for 30hours. The reaction mixture was poured into a mixture of ethyl acetateand water, and the mixture was adjusted to pH 9 with potassiumcarbonate. The separated organic layer was washed with water, dried overmagnesium sulfate and evaporated in vacuo. The residue was purified bycolumn chromatography on silica gel using a mixture of ethyl acetate andisopropyl ether (1:1 v/v) as an eluant. The eluted fractions containingthe desired product were collected and evaporated in vacuo to give2-isopropyl-4-methyl-N-(4-{[2-(2-pyridinyl)ethyl]amino}phenyl)benzamide(0.27 g).

[2062]¹H-NMR(DMSO-d₆): δ 1.20(6H, d, J=6.8 Hz), 2.33(3H, s), 2.98(2H, t,J=7.3 Hz), 3.18-3.44(3H, m), 5.53(1H, t, J=5.7 Hz), 6.57(2H, d, J=8.7Hz), 7.06(1H, d, J=7.7 Hz), 7.17-7.28(3H, m), 7.31(1H, d, J=7.7 Hz),7.44(2H, d, J=8.7 Hz), 7.71(1H, dt, J=1.6 Hz, 7.6 Hz), 8.48-8.56(1H, m),9.86(1H, s) (+)ESI-MS(m/z): 374(M+H)⁺, 396(M+Na)⁺

EXAMPLE 404

[2063] The following compound was obtained in substantially the samemanner as in Example 403.

[2064] 2-(Methylthio)-N-(4-{[2-(2-pyridinyl)ethyl]amino}phenyl)benzamide

[2065]¹H-NMR(DMSO-d₆): δ 2.42(3H, s), 2.99(2H, t, J=7.2 Hz),3.28-3.46(2H, m), 5.56(1H, s), 6.58(2H, d, J=8.8 Hz), 7.17-7.53(8H, m),7.65-7.76(1H, m), 8.48-8.57(1H, m), 9.92(1H, s) (+)ESI-MS(m/z):364(M+H)⁺, 386(M+Na)⁺

EXAMPLE 405

[2066] The following compound was obtained in substantially the samemanner as in Example 403.

[2067]4-Methyl-2-(methylthio)-N-(4-{[2-(2-pyridinyl)ethyl]amino}phenyl)benzamide

[2068]¹H-NMR(DMSO-d₆): δ 2.35(3H, s), 2.41(3H, s), 2.98(2H, t, J=7.2Hz), 3.29-3.44(2H, m), 5.54(1H, t, J=5.7 Hz), 6.57(2H, d, J=8.8 Hz),7.03(1H, d, J=7.7 Hz), 7.16-7.38(4H, m), 7.42(2H, d, J=8.8 Hz), 7.71(1H,dt, J=1.8 Hz, 7.7 Hz), 8.47-8.56(1H, m), 9.83(1H, s) (+)ESI-MS(m/z):378(M+H)⁺, 400(M+Na)⁺

[2069] Preparation 200

[2070] 1-[3-(Dimethylamino)propyl]-3-ethylcarbodiimide (2.3 g) was addedto the solution of ethyl 4-aminobenzoate (2.0 g),4-methyl-2-(4-methyl-1-piperidinyl)benzoic acid (3.1 g),1-hydroxybenzotriazole (2.0 g) and 4-dimethylaminopyridine (74 mg) intetrahydrofuran (30 ml) and the mixture was stirred at ambienttemperature for 18 hours. The reaction mixture was poured into a mixtureof ethyl acetate and water. The separated organic layer was washed withwater, dried over magnesium sulfate and evaporated in vacuo. The residuewas purified by column chromatography on silica gel using a mixture ofhexane and ethyl acetate (9:1 v/v) as an eluant. The eluted fractionscontaining the desired product were collected and evaporated in vacuo togive ethyl 4-{[4-methyl-2-(4-methyl-1-piperidinyl)benzoyl]amino}benzoate(2.5 g).

[2071]¹H-NMR(DMSO-d₆): δ 0.96(3H, d, J=6.1 Hz), 1.20-1.62(3H, m),1.32(3H, t, J=7.1 Hz), 1.65-1.81(2H, m), 2.36(3H, s), 2.70-2.88(2H, m),3.05-3.19(2H, m), 4.30(2H, q, J=7.1 Hz), 7.06(1H, d, J=7.8 Hz), 7.18(1H,s), 7.80(1H, d, J=7.8 Hz), 7.88(2H, d, J=8.8 Hz), 7.99(2H, d, J=8.8 Hz),12.17(1H, s)

[2072] Preparation 201

[2073] The mixture of ethyl4-{[4-methyl-2-(4-methyl-1-piperidinyl)benzoyl]amino}benzoate (2.4 g)and sodium hydroxide (0.38 g) in a mixture of methanol (24 ml),tetrahydrofuran (20 mL) and water (8 mL) was stirred for 2 days atambient temperature. The solvent was removed by concentration. Theresidue was diluted with water and adjusted to pH 5.5 with 6Nhydrochloric acid. The mixture was extracted with ethyl acetate. Theextract layer was washed with water, dried over magnesium sulfate andevaporated in vacuo to give4-{[4-methyl-2-(4-methyl-1-piperidinyl)benzoyl]amino}benzoic acid (2.1g).

[2074]¹H-NMR(DMSO-d₆): δ 0.96(3H, d, J=6.1 Hz), 1.20-1.63(3H, m),1.65-1.82(2H, m), 2.36(3H, s), 2.70-2.87(2H, m), 3.05-3.20(2H, m),7.05(1H, d, J=7.9 Hz), 7.18(1H, s), 7.79(1H, d, J=7.9 Hz), 7.85(2H, d,J=8.8 Hz), 7.96(2H, d, J=8.8 Hz), 12.10(1H, s), 12.74(1H, s)(+)ESI-MS(m/z): 353(M+H)⁺

EXAMPLE 406

[2075] 1-[3-(Dimethylamino)propyl]-3-ethylcarbodiimide (0.19 g) wasadded to the solution of4-{[4-methyl-2-(4-methyl-1-piperidinyl)benzoyl]amino}benzoic acid (0.35g), 2-aminopyridine (0.28 g), 1-hydroxybenzotriazole (0.16 g) and4-dimethylaminopyridine (6 mg) in tetrahydrofuran (4 ml) and the mixturewas stirred at ambient temperature for 40 hours. The reaction mixturewas poured into a mixture of ethyl acetate and water and the mixture wasadjusted to pH 9 with potassium carbonate. The separated organic layerwas washed with water, dried over magnesium sulfate and evaporated invacuo. The residue was triturated with hexane to give4-methyl-2-(4-methyl-1-piperidinyl)-N-{4-[(2-pyridinylamino)carbonyl]phenyl}benzamide(80 mg).

[2076]¹H-NMR(DMSO-d₆): δ 0.97(3H, d, J=6.0 Hz), 1.22-1.62(3H, m),1.67-1.83(2H, m), 2.36(3H, s), 2.70-2.88(2H, m), 3.05-3.21(2H, m),7.06(1H, d, J=8.0 Hz), 7.12-7.22(2H, m), 7.76-7.92(4H, m), 8.10(2H, d,J=8.7 Hz), 8.21(1H, d, J=8.4 Hz), 8.36-8.43(1H, m), 10.68(1H, s),12.11(1H, s) (+)ESI-MS(m/z): 429(M+H)⁺, 451(M+Na)⁺

EXAMPLE 407

[2077] The following compound was obtained in substantially the samemanner as in Example 406.

[2078]4-Methyl-2-(4-methyl-1-piperidinyl)-N-(4-{[(2-pyridinylmethyl)amino]carbonyl}phenyl)benzamide

[2079]¹H-NMR(DMSO-d₆): δ 0.96(3H, d, J=5.9 Hz), 1.20-1.63(3H, m),1.64-1.83(2H, m), 2.36(3H, s), 2.70-2.87(2H, m), 3.04-3.21(2H, m),4.58(2H, d, J=5.7 Hz), 7.06(1H, d, J=7.9 Hz), 7.19(1H, s), 7.27(1H, dd,J=5.4 Hz, 7.1 Hz), 7.33(1H, d, J=7.9 Hz), 7.69-8.03(6H, m),8.48-8.56(1H, m), 9.04(1H, t, J=5.7 Hz), 12.08(1H, s) (+)ESI-MS(m/z):443(M+H)⁺, 465(M+Na)⁺

EXAMPLE 408

[2080] The following compound was obtained in substantially the samemanner as in Example 406.

[2081]N-(4-{[(di-2-Pyridinylmethyl)amino]carbonyl}phenyl)-4-methyl-2-(4-methyl-1-piperidinyl)benzamide

[2082]¹H-NMR(DMSO-d₆): δ 0.96(3H, d, J=5.9 Hz), 1.23-1.63(3H, m),1.68-1.81(2H, m), 2.36(3H, s), 2.71-2.88(2H, m), 3.06-3.19(2H, m),6.46(1H, d, J=7.9 Hz), 7.06(1H, d, J=8.0 Hz), 7.19(1H, s), 7.26-7.35(2H,m), 7.55(2H, d, J=7.9 Hz), 7.74-7.90(5H, m), 8.00(2H, d, J=8.7 Hz),8.50-8.57(2H, m), 9.13(1H, d, J=7.9 Hz), 12.13(1H, s) (+)ESI-MS(m/z):520(M+H)⁺, 542(M+Na)⁺

EXAMPLE 409

[2083] The following compound was obtained in substantially the samemanner as in Example 406.

[2084]4-Methyl-2-(4-methyl-1-piperidinyl)-N-[4-({[2-(2-pyridinyl)ethyl]amino}carbonyl)phenyl]benzamide

[2085]¹H-NMR(DMSO-d₆): δ 0.96(3H, d, J=6.0 Hz), 1.20-1.63(3H, m),1.65-1.84(2H, m), 2.36(3H, s), 2.70-2.87(2H, m), 3.00(2H, t, J=7.7 Hz),3.06-3.19(2H, m), 3.54-3.70(2H, m), 7.06(1H, d, J=8.0 Hz), 7.15-7.33(3H,m), 7.65-7.93(6H, m), 8.45-8.58(2H, m), 12.07(1H, s) (+)ESI-MS(m/z):457(M+H)⁺, 479(M+Na)⁺

EXAMPLE 410

[2086] The following compound was obtained in substantially the samemanner as in Example 406.

[2087]4-Methyl-2-(4-methyl-1-piperidinyl)-N-[4-({[1-(2-pyridinyl)ethyl]amino}carbonyl)phenyl]benzamide

[2088]¹H-NMR(DMSO-d₆): δ 0.96(3H, d, J=6.0 Hz), 1.20-1.63(3H, m),1.51(3H, d, J=7.1 Hz), 1.67-1.82(2H, m), 2.36(3H, s), 2.71-2.88(2H, m),3.06-3.19(2H, m), 5.11-5.29(1H, m), 7.06(1H, d, J=7.9 Hz), 7.19(1H, s),7.21-7.30(1H, m), 7.41(1H, d, J=7.8 Hz), 7.77-7.88(4H, m), 7.96(2H, d,J=8.6 Hz), 8.50-8.56(1H, m), 8.74(1H, d, J=7.7 Hz), 12.11(1H, s)(+)ESI-MS(m/z): 457(M+H)⁺, 479(M+Na)⁺

[2089] Preparation 202

[2090] The following compound was obtained in substantially the samemanner as in Preparation 200.

[2091] Ethyl 4-{[2-(dimethylamino)-4-methylbenzoyl]amino}benzoate

[2092]¹H-NMR(DMSO-d₆): δ 1.32(3H, t, J=7.1 Hz), 2.35(3H, s), 2.77(6H,s), 4.30(2H, q, J=7.1 Hz), 6.96(1H, d, J=7.7 Hz), 7.11(1H, s), 7.66(1H,d, J=7.7 Hz), 7.86(2H, d, J=8.8 Hz), 7.95(2H, d, J=8.8 Hz), 11.83(1H, s)

[2093] Preparation 203

[2094] The following compound was obtained in substantially the samemanner as in Preparation 201.

[2095] 4-{[2-(Dimethylamino)-4-methylbenzoyl]amino}benzoic acid

[2096]¹H-NMR(DMSO-d₆): δ 2.35(3H, s), 2.77(6H, s), 6.97(1H, d, J=7.9Hz), 7.12(1H, s), 7.67(1H, d, J=7.9 Hz), 7.84(2H, d, J=8.8 Hz), 7.93(2H,d, J=8.8 Hz), 11.83(1H, s), 12.74(1H, s) (−)ESI-MS(m/z): 297(M−H)⁻

EXAMPLE 411

[2097] The following compound was obtained in substantially the samemanner as in Example 406.

[2098]2-(Dimethylamino)-4-methyl-N-[4-({[2-(2-pyridinyl)ethyl]amino}carbonyl)phenyl]benzamide

[2099]¹H-NMR(DMSO-d₆): δ 2.35(3H, s), 2.77(6H, s), 3.01(2H, t, J=7.4Hz), 3.55-3.71(2H, m), 6.97(1H, d, J=7.8 Hz), 7.12(1H, s), 7.17-7.33(2H,m), 7.65-7.90(6H, m), 8.45-8.58(2H, m), 11.76(1H, s) (+)ESI-MS(m/z):403(M+H)⁺, 425(M+Na)⁺

EXAMPLE 412

[2100] The following compound was obtained in substantially the samemanner as in Example 406.

[2101]2-(Dimethylamino)-4-methyl-N-[4-({[1-(2-pyridinyl)ethyl]amino}carbonyl)phenyl]benzamide

[2102]¹H-NMR(DMSO-d₆): δ 1.52(3H, d, J=7.0 Hz), 2.35(3H, s), 2.77(6H,s), 5.12-5.29(1H, m), 6.97(1H, d, J=7.9 Hz), 7.12(1H, s), 7.21-7.31(1H,m), 7.41(1H, d, J=7.9 Hz), 7.63-7.87(4H, m), 7.94(2H, d, J=8.6 Hz),8.49-8.57(1H, m), 8.74(1H, d, J=7.7 Hz), 11.74(1H, s) (+)ESI-MS(m/z):403(M+H)⁺, 425(M+Na)⁺

[2103] Preparation 204

[2104] 4-Nitrobenzoyl chloride (1.0 g) was added dropwise to the mixtureof [1-(2-pyridinyl)ethyl]amine (1.32 g) in acetone (13 mL) and water (8mL) at 0-8° C. under keeping to pH 7-8 with 20% aqueous potassiumcarbonate and the mixture was stirred for 2 hours at same condition. Thesolvent was removed by concentration. The residue was diluted with waterand adjusted to pH 9 with 20% aqueous potassium carbonate. The mixturewas extracted with ethyl acetate. The extract layer was washed withwater, dried over magnesium sulfate and evaporated in vacuo to give4-nitro-N-[1-(2-pyridinyl)ethyl]benzamide (0.82 g).

[2105]¹H-NMR(DMSO-d₆): δ 1.54(3H, d, J=7.1 Hz), 5.14-5.32(1H, m),7.23-7.32(1H, m), 7.44(1H, d, J=7.8 Hz), 7.72-7.84(1H, m), 8.11-8.21(2H,m), 8.28-8.38(2H, m), 8.51-8.58(1H, m), 9.11(1H, d, J=7.7 Hz)

[2106] Preparation 205

[2107] To a mixture of 4-nitro-N-[1-(2-pyridinyl)ethyl]benzamide (1.0 g)in methanol (15 ml) was added 10% palladium-on-charcoal (0.3 g, 50%wet). The reaction mixture was stirred at ambient temperature for 4hours under hydrogen atmosphere. The catalyst was filtered off and thesolvent was removed by concentration to give4-amino-N-[1-(2-pyridinyl)ethyl]benzamide (0.86 g).

[2108]¹H-NMR(DMSO-d₆): δ 1.47(3H, d, J=7.1 Hz), 5.07-5.24(1H, m),5.64(2H, s), 6.56(2H, d, J=8.6 Hz), 7.17-7.27(1H, m), 7.37(1H, d, J=7.9Hz), 7.65(2H, d, J=8.6 Hz), 7.73(1H, dt, J=1.8 Hz, 7.6 Hz), 8.33(1H, d,J=7.8 Hz), 8.47-8.55(1H, m) (+)ESI-MS(m/z): 264(M+Na)⁺

EXAMPLE 413

[2109] 1-[3-(Dimethylamino)propyl]-3-ethylcarbodiimide (0.19 g) wasadded to the solution of 4-amino-N-[1-(2-pyridinyl)ethyl]benzamide (0.24g), 6-methyl-2-(4-methyl-1-piperidinyl)nicotinic acid (0.28 g),1-hydroxybenzotriazole (0.16 g) and 4-dimethylaminopyridine (6 mg) indimethylformamide (4 ml) and the mixture was stirred at ambienttemperature for 20 hours. The reaction mixture was poured into a mixtureof ethyl acetate and water. The separated organic layer was washed withwater, dried over magnesium sulfate and evaporated in vacuo. The residuewas purified by column chromatography on silica gel using a mixture ofethyl acetate and isopropyl ether (1:1 v/v) as an eluant. The elutedfractions containing the desired product were collected and evaporatedin vacuo to give6-methyl-2-(4-methyl-1-piperidinyl)-N-[4-({[1-(2-pyridinyl)ethyl]amino}carbonyl)phenyl]nicotinamide(76.0 mg).

[2110]¹H-NMR(DMSO-d₆): δ 0.88(3H, d, J=6.1 Hz), 1.05-1.32(2H, m),1.37-1.75(3H, m), 1.51(3H, d, J=7.1 Hz), 2.40(3H, s), 2.71-2.92(2H, m),3.56-3.74(2H, m), 5.10-5.29(1H, m), 6.84(1H, d, J=7.6 Hz), 7.20-7.31(1H,m), 7.41(1H, d, J=7.9 Hz), 7.68-7.87(4H, m), 7.93(2H, d, J=8.8 Hz),8.48-8.56(1H, m), 8.73(1H, d, J=7.8 Hz), 10.74(1H, s) (+)ESI-MS(m/z):458(M+H)⁺, 480(M+Na)⁺

EXAMPLE 414

[2111] The following compound was obtained in substantially the samemanner as in Example 413.

[2112]4-Methyl-2-(4-methyl-1-piperidinyl)-N-(4-{[2-(2-pyridinyl)propanoyl]amino}phenyl)benzamide

[2113]¹H-NMR(DMSO-d₆): δ 0.95(3H, d, J=6.0 Hz), 1.20-1.63(3H, m),1.48(3H, d, J=7.0 Hz), 1.66-1.81(2H, m), 2.34(3H, s), 2.69-2.87(2H, m),3.03-3.17(2H, m), 4.01(1H, q, J=7.0 Hz), 7.04(1H, d, J=8.0 Hz), 7.16(1H,s), 7.23-7.32(1H, m), 7.45(1H, d, J=7.0 Hz), 7.56-7.73(4H, m),7.73-7.85(2H, m), 8.49-8.56(1H, m), 10.14(1H, s), 11.85(1H, s)(+)ESI-MS(m/z): 457(M+H)⁺, 479(M+Na)⁺

EXAMPLE 415

[2114] The following compound was obtained in substantially the samemanner as in Example 413.

[2115]6-Methyl-2-(4-methyl-1-piperidinyl)-N-(4-{[2-(2-pyridinyl)propanoyl]amino}phenyl)nicotinamide

[2116]¹H-NMR(DMSO-d₆): δ 0.88(3H, d, J=6.1 Hz), 1.06-1.30(2H, m),1.37-1.68(3H, m), 1.48(3H, d, J=7.0 Hz), 2.39(3H, s), 2.69-2.90(2H, m),3.56-3.71(2H, m), 4.02(1H, q, J=7.0 Hz), 6.82(1H, d, J=7.7 Hz),7.23-7.31(1H, m), 7.45(1H, d, J=7.9 Hz), 7.58(2H, d, J=9.2 Hz), 7.65(2H,d, J=9.2 Hz), 7.72-7.83(2H, m), 8.48-8.56(1H, m), 10.14(1H, s),10.49(1H, s) (+)ESI-MS(m/z): 458(M+H)⁺, 480(M+Na)⁺

EXAMPLE 416

[2117] The following compound was obtained in substantially the samemanner as in Example 403.

[2118]3-(Dimethylamino)-4-methyl-N-(4-{[2-(2-pyridinyl)ethyl]amino}phenyl)-2-thiophenecarboxamide

[2119]¹H-NMR(DMSO-d₆): δ 2.31(3H, s), 2.86(6H, s), 2.98(2H, t, J=7.2Hz), 3.30-3.44(2H, m), 5.60(1H, t, J=5.7 Hz), 6.60(2H, d, J=8.8 Hz),7.18-7.27(1H, m), 7.29-7.44(4H, m), 7.71(1H, dt, J=1.8 Hz, 7.7 Hz),8.49-8.54(1H, m), 11.54(1H, s) (+)ESI-MS(m/z): 381(M+H)⁺, 403(M+Na)⁺

EXAMPLE 417

[2120] The following compound was obtained in substantially the samemanner as in Example 403.

[2121]4-Ethyl-2-(methylamino)-N-(4-{[2-(2-pyridinyl)ethyl]amino}phenyl)benzamide

[2122]¹H-NMR(DMSO-d₆): δ 1.19(3H, t, J=7.5 Hz), 2.57(2H, q, J=7.5 Hz),2.79(3H, d, J=5.0 Hz), 2.99(2H, t, J=7.0 Hz), 3.27-3.44(2H, m), 5.53(1H,t, J=5.7 Hz), 6.41-6.52(2H, m), 6.56(2H, d, J=8.8 Hz), 7.22(1H, dd,J=5.4 Hz, 7.0 Hz), 7.27-7.43(3H, m), 7.48(1H, q, J=5.0 Hz), 7.57(1H, d,J=8.1 Hz), 7.71(1H, dt, J=1.8 Hz, 7.6 Hz), 8.48-8.54(1H, m), 9.64(1H, s)(+)ESI-MS(m/z): 375(M+H)⁺, 397(M+Na)⁺

[2123] Preparation 206

[2124] To a mixture of 2-[5-(tritylamino)-1H-pyrazol-1-yl]ethanol (4.00g) and 1-fluoro-4-nitrobenzene (1.906 g) in N,N-dimethylformamide (20ml) was added potassium tert-butoxide (1.823 g) at ambient temperature.The reaction mixture was heated to 55° C. for 1 hour, cooled to roomtemperature, poured into water and extracted with ethyl acetate. Theorganic layer was washed with water and brine, dried over magnesiumsulfate, filtered and concentrated in vacuo to yield a dark yellowsolid. The residue was suspended in ethyl acetate—hexane (1:1), filteredand washed with diisopropyl ether, then hexane to give1-[2-(4-nitrophenoxy)ethyl]-N-trityl-1H-pyrazol-5-amine (4.255 g) aspale yellow crystals.

[2125]¹H-NMR(CDCl₃): δ 4.36-4.41(2H, m), 4.44-4.49(2H, m), 4.63(1H, d,J=2.0 Hz), 5.68(1H, s), 6.45(2H, d, J=9.2 Hz), 7.03(1H, d, J=2.0 Hz),7.27(15H, s), 8.07(2H, d, J=9.2 Hz) (+)ESI-MS(m/z): 491(M+H)⁺

[2126] Preparation 207

[2127] A solution of'1-[2-(4-nitrophenoxy)ethyl]-N-trityl-1H-pyrazol-5-amine (1.000 g) inmethylalcohol—N,N-dimethylformamide (1:1) (40 ml) was hydrogenated over10% Pd/C (50% wet, 0.200 g) at 40° C. under atmospheric pressure ofhydrogen for 5 hours. The reaction mixture was filtered through a pad ofcelite, and the filtrate was concentrated in vacuo to give1-[2-(4-aminophenoxy)ethyl]-N-trityl-1H-pyrazol-5-amine (0.767 g) as apale orange powder.

[2128]¹H-NMR(CDCl₃): δ 3.38(2H, brs), 4.17-4.24(2H, m), 4.38-4.45(2H,m), 4.60(1H, d, J=2.0 Hz), 6.17(1H, brs), 6.27(2H, d, J=8.9 Hz),6.50(2H, d, J=8.9 Hz), 7.00(1H, d, J=2.0 Hz), 7.19-7.38(15H, m)(+)ESI-MS(m/z): 461(M+H)⁺, 483(M+Na)⁺

EXAMPLE 418

[2129] To a solution of 4-chloro-2-(dimethylamino)benzoic acid (184 mg),1-[2-(4-aminophenoxy)ethyl]-N-trityl-1H-pyrazol-5-amine (386 mg) and1-hydroxybenzotriazole monohydrate (167 mg) in N,N-dimethylformamide (10ml) was added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimidehydrochloride (209 mg), followed by triethylamine (110 mg) at ambienttemperature and the mixture was stirred at the same temperature for 4days. The reaction mixture was poured into a mixture of ethyl acetateand water. The separated organic layer was washed with brine, dried overmagnesium sulfate and concentrated in vacuo. The residue was suspendedin ethyl acetate—hexane (1:1), filtered and washed with hexane to give4-chloro-2-(dimethylamino)-N-(4-{2-[5-(tritylamino)-1H-pyrazol-1-yl]ethoxy}phenyl)benzamide(467 mg) as pale yellow crystals.

[2130]¹H-NMR(CDCl₃): δ 2.81(6H, s), 4.26-4.31(2H, s), 4.44-4.48(2H, m),4.61(1H, d, J=2.0 Hz), 6.08(1H, s), 6.43(2H, d, J=8.9 Hz), 7.01(1H, d,J=2.0 Hz), 7.19-7.34(17H, m), 7.44(2H, d, J=8.9 Hz), 8.16(1H, d, J=8.9Hz), 11.52(1H, s) (+)ESI-MS(m/z): 664(M+Na)⁺

EXAMPLE 419

[2131] To a solution of4-chloro-2-(dimethylamino)-N-(4-{2-[5-(tritylamino)-1H-pyrazol-1-yl]ethoxy}phenyl)benzamide(457 mg) in methanol (10 ml) was added concentrated hydrochloric acid(370 mg). The reaction mixture was stirred for 2 hours at 40° C.,quenched with 10% potassium carbonate solution, and extracted with ethylacetate. The organic layer was washed with brine, dried over magnesiumsulfate, filtered and concentrated in vacuo. The residue was suspendedin ethyl acetate—hexane (1:1), filtered and washed with hexane to giveN-{4-[2-(5-amino-1H-pyrazol-1-yl)ethoxy]phenyl}-4-chloro-2-(dimethylamino)benzamide(257 mg) as faintly brown crystals.

[2132]¹H-NMR(CDCl₃): δ 2.81(6H, s), 3.97(2H, brs), 4.28-4.33(2H, m),4.38-4.43(2H, m), 5.52(1H, d, J=2.0 Hz), 6.83(2H, d, J=8.9 Hz),7.20-7.28(3H, m), 7.55(2H, d, J=9.2 Hz), 8.15(1H, d, J=8.9 Hz),11.55(1H, brs) (+)ESI-MS(m/z): 400(M+H)⁺, 422(M+Na)⁺

EXAMPLE 420

[2133] To a solution of 2-(4-methylphenyl)-1-cyclohexene-1-carboxylicacid (186 mg), 1-[2-(4-aminophenoxy)ethyl]-N-trityl-1H-pyrazol-5-amine(360 mg) and 1-hydroxybenzotriazole monohydrate (156 mg) inN,N-dimethylformamide (10 ml) was added1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (195 mg),followed by triethylamine (103 mg) at ambient temperature and themixture was stirred at 50° C. for 8 hours. The reaction mixture waspoured into a mixture of ethyl acetate and water. The separated organiclayer was washed with brine, dried over magnesium sulfate andconcentrated in vacuo. The residue was purified by column chromatographyon silica gel eluting with hexane: ethyl acetate (1:2) to give2-(4-methylphenyl)-N-(4-{2-[5-(tritylamino)-1H-pyrazol-1-yl]ethoxy}phenyl)-1-cyclohexene-1-carboxamide(488 mg) as a colorless foamy solid.

[2134]¹H-NMR(CDCl₃): δ 1.76(4H, brs), 2.33(3H, s), 2.41(2H, brs),2.51(2H, brs), 4.17-4.21(2H, m), 4.39-4.43(2H, m), 4.58(1H, d, J=2.0Hz), 6.21(2H, d, J=8.9 Hz), 6.49(1H, brs), 6.73(2H, d, J=8.9 Hz),6.98(1H, d, J=2.0 Hz), 7.10-7.31(19H, m) (+)ESI-MS(m/z): 681(M+Na)⁺

EXAMPLE 421

[2135] To a solution of2-(4-methylphenyl)-N-(4-{2-[5-(tritylamino)-1H-pyrazol-1-yl]ethoxy}phenyl)-1-cyclohexene-1-carboxamide(476 mg) in methanol (10 ml) was added concentrated hydrochloric acid(376 mg). The reaction mixture was stirred for 1 hour at 40° C.,quenched with 10% potassium carbonate solution, and extracted with ethylacetate. The organic layer was washed with brine, dried over magnesiumsulfate, filtered and concentrated in vacuo. The residue was trituratedwith diisopropyl ether and filtered to giveN-{4-[2-(5-amino-1H-pyrazol-1-yl)ethoxy]phenyl}-2-(4-methylphenyl)-1-cyclohexene-1-carboxamide(253 mg) as a colorless powder.

[2136]¹H-NMR(CDCl₃): δ 1.76(4H, brs), 2.32(3H, s), 2.41(2H, brs),2.51(2H, brs), 3.93(2H, brs), 4.20(2H, t, J=4.6 Hz), 4.35(2H, t, J=4.6Hz), 5.49(1H, d, J=2.0 Hz), 6.63(2H, d, J=8.9 Hz), 6.85(2H, d, J=8.9Hz), 7.10-7.19(4H, m), 7.25(1H, d, J=2.0 Hz) (+)ESI-MS(m/z): 417(M+H)⁺,439(M+Na)⁺

EXAMPLE 422

[2137] To a solution of1-[2-(4-aminophenoxy)ethyl]-N-trityl-1H-pyrazol-5-amine (400 mg),4-methyl-2-(4-methyl-1-piperidinyl)benzoic acid (223 mg) and1-hydroxybenzotriazole hydrate (160 mg) in N,N-dimethylformamide (5 ml)was added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride(200 mg) and triethylamine (0.181 ml) at ambient temperature. Thereaction mixture was stirred for 15 hours at 50° C. and concentrated invacuo. The residue was dissolved in ethyl acetate and water, andextracted with ethyl acetate. The organic layer was washed with waterand brine, dried over magnesium sulfate, filtered and concentrated invacuo. The residue was purified by column chromatography on silica geleluting with hexane:ethyl acetate (1:1) to give4-methyl-2-(4-methyl-1-piperidinyl)-N-(4-{2-[5-(tritylamino)-1H-pyrazol-1-yl]ethoxy}phenyl)benzamide(552 mg) as a pale yellow foam.

[2138]¹H-NMR(CDCl₃): δ 1.05(3H, d, J=6.3 Hz), 1.35-1.45(2H, m),1.48-1.62(1H, m), 1.85(2H, d, J=8.5 Hz), 2.38(3H, s), 2.78-2.86(2H, m),3.06-3.18(2H, m), 4.29(2H, t, J=4.4 Hz), 4.47(2H, t, J=4.4 Hz), 4.60(1H,d, J=2.0 Hz), 6.17(1H, s), 6.38(2H, d, J=9.2 Hz), 7.01(1H, d, J=2.0 Hz),7.07-7.09(2H, m), 7.18-7.34(12H, m), 7.55(2H, d, J=8.9 Hz), 8.16(1H, d,J=8.2 Hz), 12.48(1H, s) ESI-MS(m/z): 698(M+Na)⁺

EXAMPLE 423

[2139] To a solution of4-methyl-2-(4-methyl-1-piperidinyl)-N-(4-{2-[5-(tritylamino)-1H-pyrazol-1-yl]ethoxy}phenyl)benzamide(366 mg) in methanol (6 ml) was added concentrated hydrochloric acid(837 mg). The reaction mixture was stirred for 14 hours at roomtemperature, quenched with 10% potassium carbonate solution andextracted with ethyl acetate. The organic layer was washed with brine,dried over magnesium sulfate, filtered and concentrated in vacuo. Theresidue was recrystallized from ethyl acetate-diisopropyl ether to giveN-(4-[2-(5-amino-1H-pyrazol-1-yl)ethoxy]phenyl}-4-methyl-2-(4-methyl-1-piperidinyl)benzamide(225 mg) as a white solid.

[2140]¹H-NMR(DMSO-d₆): δ 0.95(3H, d, J=6.3 Hz), 1.24-1.42(2H, m),1.48-1.60(1H, m), 1.73(2H, d, J=11.5 Hz), 2.34(3H, s), 2.73-2.81(2H, m),3.10(2H, d, J=11.5 Hz), 4.22(4H, s), 5.18(2H, s), 5.29(1H, d, J=2.0 Hz),6.94(2H, d, J=9.2 Hz), 7.01-7.07(2H, m), 7.16(1H, s), 7.65(2H, d, J=8.9Hz), 7.80(1H, d, J=7.9 Hz), 11.79(1H, s) ESI-MS(m/z): 434(M+H)⁺

EXAMPLE 424

[2141] The following compound was obtained in substantially the samemanner as in Example 422.

[2142]2-(Dimethylamino)-4-methyl-N-(4-{2-[5-(tritylamino)-1H-pyrazol-1-yl]ethoxy}phenyl)benzamide

[2143]¹H-NMR(CDCl₃): δ 2.39(3H, s), 2.79(6H, s), 4.28(2H, t, J=4.3 Hz),4.46(2H, t, J=4.3 Hz), 4.61(1H, d, J=2.0 Hz), 6.11(1H, s), 6.41(2H, d,J=8.9 Hz), 7.01(1H, d, J=2.0 Hz), 7.07(1H, d, J=6.9 Hz), 7.08(1H, s),7.22-7.34(15H, m), 7.46(2H, d, J=8.9 Hz), 8.14(1H, d, J=8.2 Hz),12.08(1H, s) ESI-MS(m/z): 644(M+Na)⁺

EXAMPLE 425

[2144] The following compound was obtained in substantially the samemanner as in Example 423.

[2145]N-{4-[2-(5-Amino-1H-pyrazol-1-yl)ethoxy]phenyl}-2-(dimethylamino)-4-methylbenzamide

[2146]¹H-NMR(DMSO-d₆): δ 2.33(3H, s), 2.75(6H, s), 4.22(4H, br s),5.19(2H, s), 5.29(1H, d, J=1.6 Hz), 6.89-6.94(3H, m), 7.07-7.08(2H, m),7.60-7.65(3H, m), 11.34(1H, s) ESI-MS(m/z): 402(M+Na)⁺

EXAMPLE 426

[2147] The following compound was obtained in substantially the samemanner as in Example 422.

[2148]6-Methyl-2-(4-methyl-1-piperidinyl)-N-(4-{2-[5-(tritylamino)-1H-pyrazol-1-yl]ethoxy}phenyl)nicotinamide

[2149]¹H-NMR(CDCl₃): δ 1.03(3H, d, J=6.6 Hz), 1.34-1.4(2H, m),1.55-1.65(1H, m), 1.80-1.86(2H, m), 2.51(3H, s), 2.94-3.04(2H, m),3.29-3.34(2H, m), 4.29(2H, t, J=4.3 Hz), 4.46(2H, t, J=4.3 Hz), 4.60(1H,d, J=2.0 Hz), 6.12(1H, s), 6.40(2H, d, J=8.9 Hz), 7.00(1H, s), 7.02(1H,d, J=5.6 Hz), 7.20-7.33(18H, m), 7.52(2H, d, J=9.2 Hz), 8.34(1H, d,J=7.9 Hz), 11.72(1H, s) ESI-MS(m/z): 682(M+Na)⁺

EXAMPLE 427

[2150] The following compound was obtained in substantially the samemanner as in Example 423.

[2151]N-{4-[2-(5-Amino-1H-pyrazol-1-yl)ethoxy]phenyl}-6-methyl-2-(4-methyl-1-piperidinyl)nicotinamide

[2152]¹H-NMR(DMSO-d₆): δ 0.88(3H, d, J=6.3 Hz), 1.08-1.26(2H, m),1.39-1.54(1H, m), 1.61(2H, d, J=12.2 Hz), 2.38(3H, s), 2.79(2H, t,J=11.7 Hz), 3.33-3.67(2H, m), 4.21(4H, s), 5.18(2H, s), 5.28(1H, s),6.80(1H, d, J=7.6 Hz), 6.90(2H, d, J=8.6 Hz), 7.07(1H, s), 7.62(2H, d,J=8.6 Hz), 7.73(1H, d, J=7.6 Hz), 10.41(1H, s) ESI-MS(m/z): 457(M+Na)⁺

[2153] Preparation 208

[2154] To a mixture of 2-[5-(tritylamino)-1H-pyrazol-1-yl]ethanol (2.239g) and 2-chloro-5-nitropyridine (1.059 g) in N,N-dimethylformamide (20ml) was added potassium tert-butoxide (1.021 g) at ambient temperature.The reaction mixture was stirred at the same temperature for 2 hours,poured into water and extracted with ethyl acetate. The organic layerwas washed with water and brine, dried over magnesium sulfate, filteredand concentrated in vacuo to yield dark yellow tar. The residue wasrecrystallized from ethyl acetate to give1-{2-[(5-nitro-2-pyridinyl)oxy]ethyl}-N-trityl-1H-pyrazol-5-amine (2.291g) as pale yellow crystals.

[2155]¹H-NMR(CDCl₃): δ 4.41(2H, t, J=5.5 Hz), 4.68(1H, d, J=1.6 Hz),4.70(2H, t, J=5.5 Hz), 5.44(1H, s), 6.22(1H, d, J=9.6 Hz), 7.03(1H, d,J=2.0 Hz), 7.28(15H, s), 8.16-8.23(1H, m), 8.71-8.74(1H, m)(+)ESI-MS(m/z): 514(M+Na)⁺

[2156] Preparation 209

[2157] A solution of1-{2-[(5-nitro-2-pyridinyl)oxy]ethyl}-N-trityl-1H-pyrazol-5-amine (400mg) in methanol (6 ml) and tetrahydrofuran (6 ml) was hydrogenated over10% Pd/C (50% wet, 80 mg) at 40° C. under atmospheric pressure ofhydrogen at 40° C. for 2 hours. The reaction mixture was cooled toambient temperature, added a chloroform, filtered with pad of Celite,and the filtrate was concentrated in vacuo. The residue wasrecrystallized from ethyl acetate-diisopropyl ether to give6-{2-[5-(tritylamino)-1H-pyrazol-1-yl]ethoxy}-3-pyridinamine (328 mg) asa pale yellow solid.

[2158]¹H-NMR(CDCl₃): δ 3.28(2H, br s), 4.36-4.40(2H, m), 4.45-4.49(2H,m), 4.65(1H, d, J=2.0 Hz), 5.94(1H, dd, J=8.6, 0.7 Hz), 6.02(1H, s),6.83(1H, dd, J=8.6, 3.0 Hz), 6.99(1H, d, J=2.0 Hz), 7.09(1H, d, J=2.6Hz), 7.22-7.35(15H, m) ESI-MS(m/z): 482(M+Na)⁺

EXAMPLE 428

[2159] To a solution of6-{2-[5-(tritylamino)-1H-pyrazol-1-yl]ethoxy}-3-pyridinamine (318 mg),4′-(trifluoromethyl)[1,1′-biphenyl]-2-carboxylic acid (202 mg) and1-hydroxybenzotriazole hydrate (127 mg) in N,N-dimethylformamide (5 ml)was added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride(158 mg) and triethylamine (0.144 ml) at ambient temperature. Thereaction mixture was stirred for 17 hours at 50° C. and concentrated invacuo. The residue was dissolved in ethyl acetate and water, andextracted with ethyl acetate. The organic layer was washed with waterand brine, dried over magnesium sulfate, filtered and concentrated invacuo. The residue was purified by column chromatography on silica geleluting with hexane: ethyl acetate (3:7) to give4′-(trifluoromethyl)-N-(6-{2-[5-(tritylamino)-1H-pyrazol-1-yl)ethoxy}-3-pyridinyl)-1,1′-biphenyl-2-carboxamide(430 mg) as a pale yellow foam.

[2160]¹H-NMR(CDCl₃): δ 4.37(2H, t, J=4.9 Hz), 4.50(2H, t, J=4.9 Hz),4.61(1H, d, J=2.0 Hz), 5.89(1H, d, J=6.9 Hz), 5.93(1H, s), 6.90-6.96(2H,m), 7.18-7.32(16H, m), 7.43-7.61(7H, m), 7.68(2H, d, J=8.2 Hz), 7.77(1H,d, J=7.6 Hz) ESI-MS(m/z): 732(M+Na)⁺

EXAMPLE 429

[2161] To a solution of4′-(trifluoromethyl)-N-(6-{2-[5-(tritylamino)-1H-pyrazol-1-yl]ethoxy}-3-pyridinyl)-1,1′-biphenyl-2-carboxamide(420 mg) in methanol (6 ml) was added concentrated hydrochloric acid(617 mg). The reaction mixture was stirred for 14 hours at ambienttemperature, quenched with 10% potassium carbonate solution andextracted with ethyl acetate. The organic layer was washed with brine,dried over magnesium sulfate, filtered and concentrated in vacuo. Theresidue was recrystallized from ethyl acetate-diisopropyl ether to giveN-{6-[2-(5-amino-1H-pyrazol-1-yl)ethoxy]-3-pyridinyl}-4′-(trifluoromethyl)-1,1′-biphenyl-2-carboxamide(173 mg) as a white solid.

[2162]¹H-NMR(DMSO-d₆): δ 4.20(2H, t, J=5.9 Hz), 4.44(2H, t, J=5.9 Hz),5.15(2H, s), 5.27(1H, d, J=2.0.Hz), 6.77(1H, d, J=8.9 Hz), 7.04(1H, d,J=1.7 Hz), 7.51-7.75(6H, m), 7.77(2H, d, J=9.2 Hz), 7.82(1H, d, J=2.9Hz), 8.27(1H, d, J=2.7 Hz), 10.39(1H, s) ESI-MS(m/z): 468(M+H)⁺

EXAMPLE 430

[2163] To a solution of 2-(4-methylphenyl)-1-cyclohexene-1-carboxylicacid (384 mg) in toluene (5 ml) were added thionyl chloride (342 mg) andN,N-dimethylformamide (1 drop) and the mixture was stirred at 50° C. for1 hour. The mixture was evaporated in vacuo and the residue wasdissolved in tetrahydrofuran (2 ml). The acid chloride intetrahydrofuran was added to a solution of6-{2-[5-(tritylamino)-1H-pyrazol-1-yl]ethoxy}-3-pyridinamine (363 mg)and triethylamine (0.25 ml) in tetrahydrofuran (8 ml) at ambienttemperature and the mixture was stirred at the same temperature for 1hour. The mixture was poured into water and extracted with ethylacetate. The organic layer was washed with brine, dried over magnesiumsulfate and evaporated in vacuo. The residue was purified by columnchromatography on silica gel eluting with hexane:ethyl acetate (1:1) togive2-(4-methylphenyl)-N-(6-{2-[5-(tritylamino)-1H-pyrazol-1-yl]ethoxy}-3-pyridinyl)-1-cyclohexene-1-carboxamide(443 mg) as a yellow foam.

[2164]¹H-NMR(CDCl₃): δ 1.77(4H, br s), 2.32(3H, s), 2.42(2H, br s),2.50(2H, br s), 4.37(2H, t, J=4.6 Hz), 4.49(2H, t, J=4.6 Hz), 4.59(1H,d, J=2.0 Hz), 5.80(1H, d, J=8.9 Hz), 5.86(1H, s), 6.46(1H, s), 6.98(1H,d, J=2.0 Hz), 7.12-7.15(5H, m), 7.20-7.30(17H, m), 7.46(1H, dd, J=8.9,2.6 Hz) ESI-MS (m/z): 682 (M+Na)⁺

EXAMPLE 431

[2165] To a solution of2-(4-methylphenyl)-N-(6-{2-[5-(tritylamino)-1H-pyrazol-1-yl]ethoxy}-3-pyridinyl)-1-cyclohexene-1-carboxamide(420 mg) in methanol (6 ml) was added concentrated hydrochloric acid(617 mg). The reaction mixture was stirred for 14 hours at ambienttemperature, quenched with 10% potassium carbonate solution, andextracted with ethyl acetate. The organic layer was washed with brine,dried over magnesium sulfate, filtered and concentrated in vacuo. Theresidue was recrystallized from ethyl acetate-diisopropyl ether to giveN-{6-[2-(5-amino-1H-pyrazol-1-yl)ethoxy]-3-pyridinyl}-2-(4-methylphenyl)-1-cyclohexene-1-carboxamide(204 mg) as a pale yellow solid.

[2166]¹H-NMR(DMSO-d₆): δ 1.71(4H, br s), 2.21(3H, s), 2.35(4H, br s),4.17(2H, t, J=5.7 Hz), 4.40(2H, t, J=5.7 Hz), 5.15(2H, s), 5.26(1H, s),6.68(1H, d, J=8.9 Hz), 7.03(1H, s), 7.05(2H, d, J=8.9 Hz), 7.17(1H, d,J=7.9 Hz), 7.64(1H, dd, J=8.9, 1.4 Hz), 8.08(1H, s), 9.52(1H, s)ESI-MS(m/z): 418(M+H)⁺

EXAMPLE 432

[2167] To a solution of tert-butyl4-aminophenyl[2-(1H-pyrazol-1-yl)ethyl]carbamate (264 mg),4-chloro-2-(dimethylamino)benzoic acid (286 mg) and1-hydroxybenzotriazole hydrate (221 mg) in N,N-dimethylformamide (7 ml)was added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride(276 mg) at ambient temperature. The reaction mixture was stirred for 16hours at 40° C., cooled and concentrated in vacuo. The residue wasdissolved in ethyl acetate and water, and extracted with ethyl acetate.The organic layer was washed with water and brine, dried over magnesiumsulfate, filtered and concentrated in vacuo. The residue was purified bycolumn chromatography on silica gel eluting with hexane: ethyl acetate(1:1) to give tert-butyl4-{[4-chloro-2-(dimethylamino)benzoyl]amino}phenyl[2-(1H-pyrazol-1-yl)ethyl]carbamate(451 mg) as a colorless foam.

[2168]¹H-NMR(CDCl₃): δ 1.41(9H, s), 2.82(6H, s), 4.03(2H, t, J=6.3 Hz),4.34(2H, t, J=5.9 Hz), 6.24(1H, t, J=2.0 Hz), 6.93(2H, br s), 7.23(1H,dd, J=7.9, 2.0 Hz), 7.40(1H, d, J=2.0 Hz), 7.49(1H, d, J=1.3 Hz),7.57(2H, d, J=8.6 Hz), 8.16(1H, dd, J=7.9, 1.3 Hz), 11.71(1H, s)ESI-MS(m/z): 506(M+Na)⁺

EXAMPLE 433

[2169] To a solution of tert-butyl4-{[4-chloro-2-(dimethylamino)benzoyl]amino}phenyl[2-(1H-pyrazol-1-yl)ethyl]carbamate(437 mg) in dichloromethane (15 ml) was added trifluoroacetic acid (1.04ml). The reaction mixture was stirred for 18 hours at ambienttemperature, quenched with 10% potassium carbonate solution andextracted with dichloromethane. The organic layer was washed with brine,dried over magnesium sulfate, filtered and concentrated in vacuo. Theresidue was recrystallized from ethyl acetate-diisopropyl ether to give4-chloro-2-(dimethylamino)-N-(4-{[2-(1H-pyrazol-1-yl)ethyl]amino}phenyl)benzamide(200 mg) as yellow solids.

[2170]¹H-NMR(DMSO-d₆): δ 2.79(6H, s), 3.41(2H, q, J=6.3 Hz), 4.25(2H, t,J=6.3 Hz), 5.61(1H, t, J=6.1 Hz), 6.22(1H, t, J=2.0 Hz), 6.56(2H, d,J=8.9 Hz), 7.00(1H, dd, J=7.9, 2.0 Hz), 7.07(1H, d, J=2.0 Hz), 7.41(2H,d, J=8.9 Hz), 7.46(1H, d, J=1.3 Hz), 7.51(1H, d, J=8.2 Hz), 7.73(1H, d,J=2.3 Hz), 10.40(1H, s) ESI-MS(m/z): 406(M+Na)⁺

EXAMPLE 434

[2171] The following compound was obtained in substantially the samemanner as in Example 432.

[2172] tert-Butyl(2-{6-[(tert-butoxycarbonyl)amino]-2-pyridinyl}ethyl)(4-{[4-chloro-2-(dimethylamino)benzoyl]amino}phenyl)carbamate

[2173]¹H-NMR(CDCl₃): δ 1.42(18H, s), 2.83(6H, s), 3.04(2H, t, J=7.9 Hz),3.94(2H, t, J=7.9 Hz), 7.08(2H, d, J=7.9 Hz), 7.16(2H, d, J=8.6 Hz),7.24(1H, dd, J=7.9, 2.3 Hz), 7.58-7.64(3H, m), 8.17(1H, dd, J=7.9, 1.3Hz), 11.69(1H, s) ESI-MS(m/z): 633(M+Na)⁺

EXAMPLE 435

[2174] The following compound was obtained in substantially the samemanner as in Example 433.

[2175]N-(4-{[2-(6-Amino-2-pyridinyl)ethyl]amino}phenyl)-4-chloro-2-(dimethylamino)benzamide

[2176]¹H-NMR(DMSO-d₆): δ 2.73(2H, t, J=7.3 Hz), 2.79(6H, s), 3.27(2H, t,J=7.3 Hz), 5.59(1H, br s), 5.85(2H, br s), 6.27(1H, d, J=7.9 Hz),6.40(1H, d, J=0.9 Hz), 6.57(2H, d, J=8.9 Hz), 7.02(1H, dd, J=8.2, 2.0Hz), 7.08(1H, d, J=2.0 Hz), 7.27(1H, dd, J=7.9, 7.3 Hz), 7.40(2H, d,J=8.9 Hz), 7.50(1H, d, J=7.3 Hz), 10.39(1H, s) ESI-MS(m/z): 410(M+H)⁺

EXAMPLE 436

[2177] The following compound was obtained in substantially the samemanner as in Example 432.

[2178] tert-Butyl{6-[2-(4-{[4-chloro-2-(dimethylamino)benzoyl]amino}phenoxy)ethyl]-2-pyridinyl}carbamate

[2179]¹H-NMR(CDCl₃): δ 1.51(9H, s), 2.82(3H, s), 3.13(2H, t, J=6.7 Hz),4.30(2H, t, J=6.7 Hz), 6.86-6.92(3H, m), 7.21(1H, dd, J=7.9, 2.0 Hz),7.23(1H, s), 7.54(2H, d, J=8.9 Hz), 7.60(1H, d, J=7.9 Hz), 7.77(1H, d,J=8.2 Hz), 8.14-8.17(1H, m), 11.48(1H, s) ESI-MS(m/z): 534(M+Na)⁺

EXAMPLE 437

[2180] The following compound was obtained in substantially the samemanner as in Example 433.

[2181]N-{4-[2-(6-Amino-2-pyridinyl)ethoxy]phenyl}-4-chloro-2-(dimethylamino)benzamide

[2182]¹H-NMR(DMSO-d₆): δ 2.79(6H, s), 2.91(2H, t, J=6.7 Hz), 4.23(2H, t,J=6.7 Hz), 5.85(2H, s), 6.28(1H, d, J=8.2 Hz), 6.44(1H, d, J=6.9 Hz),6.91(2H, d, J=8.9 Hz), 6.99(1H, dd, J=8.2, 2.0 Hz), 7.08(1H, d, J=2.0Hz), 7.28(1H, dd, J=7.3, 6.9 Hz), 7.49(1H, d, J=8.2 Hz), 7.60(2H, d,J=8.9 Hz), 10.56(1H, s) ESI-MS(m/z): 411(M+H)⁺

EXAMPLE 438

[2183] The following compound was obtained in substantially the samemanner as in Example 432.

[2184] tert-Butyl(2-{2-[(tert-butoxycarbonyl)amino]-1,3-thiazol-4-yl}ethyl)(4-{[4-chloro-2-(dimethylamino)benzoyl]amino}phenyl)carbamate

[2185]¹H-NMR(CDCl₃): δ 1.49(18H, s), 2.83(6H, s), 2.95(2H, t, J=7.2 Hz),3.92(2H, t, J=7.2 Hz), 6.78(1H, s), 7.14(2H, d, J=8.2 Hz), 7.21-7.26(3H,m), 7.61(2H, d, J=8.9 Hz), 8.17(1H, dd, J=7.6, 1.0 Hz), 11.70(1H, s)ESI-MS(m/z): 739(M+Na)⁺

EXAMPLE 439

[2186] The following compound was obtained in substantially the samemanner as in Example 433.

[2187]N-(4-{[2-(2-Amino-1,3-thiazol-4-yl)ethyl]amino}phenyl)-4-chloro-2-(dimethylamino)benzamide

[2188]¹H-NMR(DMSO-d₆): δ 2.66(2H, t, J=7.3 Hz), 2.79(6H, s), 3.22(2H, t,J=7.3 Hz), 5.51(1H, br s), 6.21(1H, s), 6.55(2H, d, J=8.6 Hz), 6.87(2H,s), 7.08(1H, dd, J=8.2, 2.0 Hz), 7.41(2H, d, J=8.9 Hz), 7.52(1H, d,J=8.2 Hz), 10.40(1H, s) ESI-MS(m/z): 416(M+H)⁺

EXAMPLE 440

[2189] To a solution ofN-{2-[3-(tritylamino)-1H-pyrazol-1-yl]ethyl}-1,4-benzenediamine (131mg), 4-chloro-2-(dimethylamino)benzoic acid (62.6 mg) and1-hydroxybenzotriazole (48 mg) in N,N-dimethylformamide (1.3 ml) wasadded 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride(60.1 mg), followed by triethylamine (43.3 mg) at ambient temperature.The reaction mixture was stirred for 14 hours at 50° C. and concentratedin vacuo. The residue was dissolved in ethyl acetate and water, andextracted with ethyl acetate. The organic layer was washed with waterand brine, dried over magnesium sulfate, filtered and concentrated invacuo. The residue was purified by column chromatography on silica geleluting with hexane:ethyl acetate (1:1) to give4-chloro-2-(dimethylamino)-N-[4-({2-[3-(tritylamino)-1H-pyrazol-1-yl]ethyl}amino)phenyl]benzamide(0.157 g) as a yellow foam.

[2190]¹H-NMR(CDCl₃): δ 2.81(6H, s), 3.39(2H, t, J=5.7 Hz), 3.99(2H, t,J=5.4 Hz), 4.91(1H, d, J=2.4 Hz), 5.43(2H, br s), 6.48(2H, d, J=8.9 Hz),6.76(1H, d, J=2.4 Hz), 7.16-7.32(11H, m), 7.36-7.43(8H, m), 8.14(1H, d,J=8.9 Hz), 11.37(1H, s) ESI-MS(m/z): 664(M+Na)⁺

EXAMPLE 441

[2191] To a solution of4-chloro-2-(dimethylamino)-N-[4-({2-[3-(tritylamino)-1H-pyrazol-1-yl]ethyl}amino)phenyl]benzamide(150 mg) in methanol (1.2 ml) was added 35% hydrochloric acid (0.104ml). The mixture was stirred for 3 hours and concentrated in vacuo. Theresidue was dissolved in ethyl acetate and 10% potassium carbonatesolution, and extracted with ethyl acetate. The organic layer was washedwith brine, dried over magnesium sulfate, filtered and concentrated invacuo. The residue was recrystallized from hexane-ethyl acetate to giveN-(4-{[2-(3-amino-1H-pyrazol-1-yl)ethyl]amino}phenyl)-4-chloro-2-(dimethylamino)benzamide(0.073 g) as pale yellow powder.

[2192]¹H-NMR(CDCl₃): δ 2.82(6H, s), 3.53(2H, t, J=5.4 Hz), 4.12(2H, t,J=5.1 Hz), 5.58(1H, d, J=2.2 Hz), 6.62(2H, d, J=8.9 Hz), 7.09(1H, d,J=2.4 Hz), 7.19-7.23(2H, m), 7.47(2H, d, J=8.6 Hz), 8.15(1H, d, J=8.9Hz), 11.35(1H, s) ESI-MS(m/z): 399(M+H)⁺

[2193] Preparation 210

[2194] The mixture of 1-(2-aminoethyl)-N-trityl-1H-pyrazol-3-amine(5.276 g), 2-chloro-5-nitropyridine (2.72 g) and triethylamine (3.99 ml)in dimethylformamide (26.4 ml) was heated to 50° C. for 18 hours. Thereaction mixture was concentrated in vacuo. To the residue added waterand extracted with ethyl acetate. The organic layer was washed withbrine, dried over magnesium sulfate, filtered and concentrated in vacuo.The residue was recrystallized from ethyl acetate-hexane to give5-nitro-N-{2-[3-(tritylamino)-1H-pyrazol-1-yl]ethyl}-2-pyridinamine(6.812 g) as pale yellow powder.

[2195]¹H-NMR(CDCl₃): δ 3.68(2H, br q, J=5.1 Hz), 3.97(2H, br t, J=5.1Hz), 5.04(1H, d, J=2.2 Hz), 5.09(1H, s), 5.69(1H, br s), 6.06(1H, d,J=9.5 Hz), 6.81(1H, d, J=2.4 Hz), 7.16-7.30(10H, m), 7.36-7.47(6H, m),8.08(1H, dd, J=9.2, 2.7 Hz), 8.98(1H, d, J=2.7 Hz) ESI-MS(m/z):513(M+H)⁺

[2196] Preparation 211

[2197] A solution of5-nitro-N-{2-[3-(tritylamino)-1H-pyrazol-1-yl]ethyl}-2-pyridinamine (2.5g) in methanol (25 ml) was hydrogenated over 10% palladium on carbon(0.5 g 50% wet) at ambient temperature under atmospheric pressure ofhydrogen for 11 hours. The reaction mixture was filtered through a shortpad of celite, and the filtrate was concentrated in vacuo to give5-amino-2-({2-[3-(tritylamino)-1H-pyrazol-1-yl]ethyl}amino)pyridine (2.3g) as a dark purple foam.

[2198]¹H-NMR(CDCl₃): δ 3.50(2H, br q, J=5.1 Hz), 3.96(2H, br t, J=5.1Hz), 4.05(1H, br s), 4.91(1H, d, J=2.2 Hz), 5.11(1H, s), 5.14(1H, dd,J=8.6, 0.8 Hz), 6.75(1H, d, J=2.4 Hz), 6.98(1H, dd, J=8.4, 3.0 Hz),7.19-7.29(9H, m), 7.38-7.43(6H, m), 7.65(1H, d, J=2.7 Hz) ESI-MS(m/z):483(M+Na)⁺

EXAMPLE 442

[2199] To a solution of5-amino-2-({2-[3-(tritylamino)-1H-pyrazol-1-yl]ethyl}amino)pyridine (218mg), 4-chloro-2-(dimethylamino)benzoic acid (104 mg) and1-hydroxybenzotriazole (79.7 mg) in N,N-dimethylformamide (2.2 ml) wasadded 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride(99.8 mg), followed by triethylamine (0.1 ml) at ambient temperature.The reaction mixture was stirred for 12 hours at 60° C. and concentratedin vacuo. The residue was dissolved in ethyl acetate and water, andextracted with ethyl acetate. The organic layer was washed with waterand brine, dried over magnesium sulfate, filtered and concentrated invacuo to give4-chloro-2-(dimethylamino)-N-[6-({2-[3-(tritylamino)-1H-pyrazol-1-yl]ethyl}amino)-3-pyridinyl]benzamide(0.271 g) as a dark red foam.

[2200]¹H-NMR(CDCl₃): δ 2.81(6H, s), 3.61(2H, t, J=5.4 Hz), 4.04(2H, t,J=6.5 Hz), 4.88(1H, d, J=2.7 Hz), 6.33(1H, d, J=8.9 Hz), 6.82(1H, d,J=2.2 Hz), 7.16-7.45(18H, m), 7.98(1H, dd, J=8.9, 2.2 Hz), 8.14-8.17(2H,m), 11.70(1H, s) ESI-MS(m/z): 643(M+H)⁺

EXAMPLE 443

[2201] To a solution of4-chloro-2-(dimethylamino)-N-[6-({2-[3-(tritylamino)-1H-pyrazol-1-yl]ethyl}amino)-3-pyridinyl]benzamide(217.4 mg) in methanol (2.2 ml) was added 35% hydrochloric acid (0.185ml). The mixture was stirred for 2 hours and concentrated in vacuo. Theresidue was dissolved in ethyl acetate and 10% potassium carbonatesolution and extracted with ethyl acetate. The organic layer was washedwith brine, dried over magnesium sulfate, filtered and concentrated invacuo. The residue was purified by column chromatography on silica geleluting with chloroform: methanol (19:1) to giveN-(6-{[2-(3-amino-1H-pyrazol-1-yl)ethyl]amino}-3-pyridinyl)-4-chloro-2-(dimethylamino)benzamide(0.092 g) as pale brown powder.

[2202]¹H-NMR(CDCl₃): δ 2.82(6H, s), 3.73(2H, br q, J=5.9 Hz), 4.14(2H,t, J=5.1 Hz), 4.77(1H, br s), 5.57(1H, d, J=2.4 Hz), 6.42(1H, d, J=8.9Hz), 7.09(1H, d, J=2.2 Hz), 7.21-7.27(2H, m), 7.99(1H, dd, J=8.9, 2.4Hz), 8.14-8.18(2H, m), 11.56(1H, s) ESI-MS(m/z): 400(M+H)⁺

[2203] Preparation 212

[2204] To a solution of 2-(5-amino-1H-pyrazol-1-yl)ethanol (10 g) in1,2-dichloroethane (100 ml) was added triethylamine (12.1 mL) and tritylchloride (24.1 g) at ambient temperature. The mixture was stirred atroom temperature for 3 hours. The reaction mixture was poured intowater, filtered, and washed with hexane. The solid was dissolved withethyl acetate at 70° C., recrystallized from hexane to give2-[5-(tritylamino)-1H-pyrazol-1-yl]ethanol (18.246 g) as white powder.

[2205]¹H-NMR(CDCl₃): δ 3.65(1H, br s), 3.81(2H, t, J=4.6 Hz), 3.95(2H,t, J=4.9 Hz), 4.77(1H, d, J=2.2 Hz), 5.76(1H, s), 6.96(1H, d, J=1.9 Hz),7.18-7.33(15H, m) ESI-MS(m/z): 370(M+H)⁺

[2206] Preparation 213

[2207] To a solution of 2-[5-(tritylamino)-1H-pyrazol-1-yl]ethanol (12g) in 1,2-dichloroethane (120 ml) was added triethylamine (6.79 ml) and4-(N,N-dimethylamino)pyridine (0.4 g), followed by p-toluenesulfonylchloride (7.43 g). The mixture was stirred at ambienttemperature for 16 hours. The reaction mixture was poured into water andextracted with 1,2-dichloroethane. The organic layer was washed withbrine, dried over magnesium sulfate, filtered and concentrated in vacuo.The residue was recrystallized from ethyl acetate-hexane to give2-[5-(tritylamino)-1H-pyrazol-1-yl]ethyl 4-methylbenzenesulfonate(13.055 g) as white powder.

[2208]¹H-NMR(CDCl₃): δ 2.41(3H, s), 4.16(2H, t, J=4.9 Hz), 4.29(2H, t,J=4.6 Hz), 4.82(1H, d, J=1.9 Hz), 5.01(1H, s), 6.98(1H, d, J=2.2 Hz),7.19-7.30(17H, m), 7.55(2H, d, J=8.1 Hz) ESI-MS(m/z): 546(M+Na)⁺

[2209] Preparation 214

[2210] To a solution of 2-[5-(tritylamino)-1H-pyrazol-1-yl]ethyl4-methylbenzenesulfonate (12.0 g) in N,N-dimethylformamide (120 ml) wasadded sodium azide (2.98 g). The mixture was stirred at ambienttemperature for 12 hours. The reaction mixture was concentrated invacuo, poured into water and extracted with ethyl acetate. The organiclayer was washed with brine, dried over magnesium sulfate, filtered andconcentrated in vacuo. The residue was recrystallized from ethylacetate-hexane to give 1-(2-azidoethyl)-N-trityl-1H-pyrazol-5-amine(9.00 g) as pale yellow powder.

[2211]¹H-NMR(CDCl₃): δ 3.69(2H, t, J=5.4 Hz), 3.99(2H, t, J=5.7 Hz),4.86(1H, d, J=1.6 Hz), 5.19(1H, s), 7.08(1H, d, J=1.9 Hz),7.18-7.32(15H, m) ESI-MS(m/z): 395(M+H)⁺

[2212] Preparation 215

[2213] A solution of 1-(2-azidoethyl)-N-trityl-1H-pyrazol-5-amine (4.226g) in methanol (42 ml) was hydrogenated over 10% palladium on carbon(0.845 g, 50% wet) at ambient temperature under atmospheric pressure ofhydrogen for 1.5 hours. The reaction mixture was filtered through ashort pad of celite, and the filtrate was concentrated in vacuo. Theresidue was purified by column chromatography on silica gel eluting withhexane: ethyl acetate (1:3) to giveN-[1-(2-aminoethyl)-1H-pyrazol-5-yl]-N-tritylamine (2.139 g) as whitepowder.

[2214]¹H-NMR(CDCl₃): δ 3.07(2H, t, J=5.4 Hz), 4.01(2H, t, J=5.1 Hz),4.74(1H, d, J=1.9 Hz), 6.82(1H, br s), 7.01(1H, d, J=2.2 Hz),7.18-7.35(15H, m) ESI-MS(m/z): 369(M+H)⁺

[2215] Preparation 216

[2216] To a solution ofN-[1-(2-aminoethyl)-1H-pyrazol-5-yl]-N-tritylamine (2.139 g) in1,3-dimethyl-2-imidazolidinone (21 ml) was added to triethylamine (1.21ml), followed by 1-fluoro-4-nitrobenzene (0.983 g) at ambienttemperature. The mixture was stirred at 50° C. for 20 hours. Thereaction mixture was cooled to ambient temperature, poured into waterand extracted with ethyl acetate. The organic layer was washed withbrine, dried over magnesium sulfate, filtered and concentrated in vacuo.The residue was recrystallized from ethyl acetate-hexane to give1-{2-[(4-nitrophenyl)amino]ethyl}-N-trityl-1H-pyrazol-5-amine (2.119 g)as a yellow powder.

[2217]¹H-NMR(CDCl₃): δ 3.53(2H, br q, J=5.4 Hz), 4.06(2H, t, J=5.4 Hz),4.42(1H, s), 4.91(1H, d, J=1.9 Hz), 5.18(1H, br t, J=5.1 Hz), 6.45(2H,d, J=9.2 Hz), 7.12-7.26(16H, m), 8.03(2H, d, J=8.9 Hz) ESI-MS(m/z):512(M+Na)⁺

[2218] Preparation 217

[2219] To a solution of1-{2-[(4-nitrophenyl)amino]ethyl}-N-trityl-1H-pyrazol-5-amine (2.114 g)and 4-(N,N-dimethylamino)pyridine (52.8 mg) in tetrahydrofuran (21 ml)was added di-t-butyl dicarbonate (1.13 g). The mixture was stirred at40° C. for 15 hours. The reaction mixture was cooled to ambienttemperature and concentrated in vacuo. The residue was dissolved inethyl acetate and water, and extracted with ethyl acetate. The organiclayer was washed with brine, dried over magnesium sulfate, filtered andconcentrated in vacuo. The residue was recrystallized from ethylacetate-hexane to give tert-butyl4-nitrophenyl{2-[5-(tritylamino)-1H-pyrazol-1-yl]ethyl}carbamate (2.363g) as pale yellow powder.

[2220]¹H-NMR(CDCl₃): δ 1.34(9H, s), 3.96(2H, t, J=5.9 Hz), 4.15(2H, t,J=6.2 Hz), 4.82(1H, d, J=2.2 Hz), 5.05(1H, br s), 7.00(1H, d, J=1.9 Hz),7.04(2H, d, J=9.2 Hz), 7.18-7.33(15H, m), 8.07(2H, d, J=9.2 Hz)ESI-MS(m/z): 612(M+Na)⁺

[2221] Preparation 218

[2222] A solution of tert-butyl4-nitrophenyl{2-[5-(tritylamino)-1H-pyrazol-1-yl]ethyl}carbamate (2.363g) in ethyl acetate (24 ml) was hydrogenated over 10% palladium oncarbon (0.473 g 50% wet) at room temperature under atmospheric pressureof hydrogen for 3 hours. The reaction mixture was filtered through ashort pad of celite, and the filtrate was concentrated in vacuo. Theresidue was purified by column chromatography on silica gel eluting withhexane: ethyl acetate (4:1→1/1→1/2) to give tert-butyl4-aminophenyl{2-[5-(tritylamino)-1H-pyrazol-1-yl]ethyl}carbamate (2.177g) as a pale yellow foam.

[2223]¹H-NMR(CDCl₃): δ 1.26(9H, s), 3.64(2H, br s), 3.76(2H, t, J=7.3Hz), 4.13(2H, t, J=7.3 Hz), 4.76(1H, br s), 6.53(2H, d, J=8.4 Hz),6.73(2H, br d, J=8.4 Hz), 6.98(1H, d, J=2.2 Hz), 7.18-7.29(9H, m),7.35-7.37(6H, m) ESI-MS(m/z): 582(M+Na)⁺

EXAMPLE 444

[2224] To a solution of tert-butyl4-aminophenyl{2-[5-(tritylamino)-1H-pyrazol-1-yl]ethyl}carbamate (400mg), 4-chloro-2-(dimethylamino)benzoic acid (157 mg) and1-hydroxybenzotriazole (120 mg) in N,N-dimethylformamide (4 ml) wasadded 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (151mg), followed by triethylamine (0.15 ml) at ambient temperature. Thereaction mixture was stirred for 16 hours at 60° C. and concentrated invacuo. The residue was dissolved in ethyl acetate and water andextracted with ethyl acetate. The organic layer was washed with waterand brine, dried over magnesium sulfate, filtered and concentrated invacuo. The residue was purified by column chromatography on silica geleluting with hexane: ethyl acetate (3:1→1:1) to give tert-butyl4-{[4-chloro-2-(dimethylamino)benzoyl]amino}phenyl{2-[5-(tritylamino)-1H-pyrazol-1-yl]ethyl}carbamate(424 mg) as a pale yellow foam.

[2225]¹H-NMR(CDCl₃): δ 1.29(9H, s), 3.82(2H, t, J=7.0 Hz), 4.23(2H, t,J=6.5 Hz), 4.76(1H, d, J=2.2 Hz), 6.92(2H, d, J=8.9 Hz), 6.97(1H, d,J=2.2 Hz), 7.20-7.39(17H, m), 7.54(2H, d, J=8.6 Hz), 8.17(1H, d, J=8.9Hz), 11.74(1H, s) ESI-MS(m/z): 764(M+Na)⁺

EXAMPLE 445

[2226] To a solution of tert-butyl4-([4-chloro-2-(dimethylamino)benzoyl]amino}phenyl{2-[5-(tritylamino)-1H-pyrazol-1-yl]ethyl}carbamate(416 mg) in dichloromethane (4.2 ml) was added trifluoroacetic acid(0.648 ml). The reaction mixture was stirred for 7 hours, quenched with10% potassium carbonate solution and extracted with dichloromethane. Theorganic layer was washed with brine, dried over magnesium sulfate,filtered and concentrated in vacuo. The residue was purified by columnchromatography on silica gel eluting with hexane: ethyl acetate(1:1→1:3→1:5) to giveN-(4-{[2-(5-amino-1H-pyrazol-1-yl)ethyl]amino}phenyl)-4-chloro-2-(dimethylamino)benzamide(148 mg) as pale yellow powder.

[2227]¹H-NMR(CDCl₃): δ 2.82(6H, s), 3.58(2H, dd, J=5.7, 4.3 Hz),4.19(2H, t, J=5.1 Hz), 5.52(1H, d, J=2.2 Hz), 6.59(2H, d, J=8.9 Hz),7.21(1H, dd, J=7.6, 1.9 Hz), 7.23(1H, s), 7.31(1H, d, J=1.9 Hz),7.46(2H, d, J=8.9 Hz), 8.15(1H, d, J=9.2 Hz), 11.39(1H, s) ESI-MS(m/z):339(M+H)⁺

EXAMPLE 446

[2228] The following compound was obtained in substantially the samemanner as in Example 444.

[2229] tert-Butyl(4-{[2-(dimethylamino)-4-methylbenzoyl]amino}phenyl){2-[5-(tritylamino)-1H-pyrazol-1-yl]ethyl}carbamate

[2230]¹H-NMR(CDCl₃): δ 1.28(9H, s), 2.40(3H, s), 2.81(6H, s), 3.82(2H,t, J=6.2 Hz), 4.21(2H, t, J=5.9 Hz), 4.76(1H, d, J=1.9 Hz), 6.91(2H, d,J=8.6 Hz), 6.98(1H, d, J=2.4 Hz), 7.09(1H, d, J=7.8 Hz), 7.10(1H, s),7.17-7.37(15H, m), 7.56(2H, d, J=8.9 Hz), 8.15(1H, d, J=8.4 Hz),12.31(1H, s) ESI-MS(m/z): 743(M+H)⁺

EXAMPLE 447

[2231] The following compound was obtained in substantially the samemanner as in Example 445.

[2232]N-(4-{[2-(5-Amino-1H-pyrazol-1-yl)ethyl]amino}phenyl)-2-(dimethylamino)-4-methylbenzamide

[2233]¹H-NMR(CDCl₃): δ 2.39(3H, s), 2.80(6H, s), 3.58(2H, t, J=5.4 Hz),4.18(2H, t, J=5.1 Hz), 5.51(1H, d, J=1.9 Hz), 6.59(2H, d, J=8.9 Hz),7.07(1H, d, J=7.0 Hz), 7.08(1H, s), 7.31(1H, d, J=1.9 Hz), 7.49(2H, d,J=8.9 Hz), 8.14(1H, d, J=8.4 Hz), 11.94(1H, br s) ESI-MS(m/z):401(M+Na)⁺

EXAMPLE 448

[2234] The following compound was obtained in substantially the samemanner as in Example 444.

[2235] tert-Butyl[4-({[6-methyl-2-(4-methyl-1-piperidinyl)-3-pyridinyl]carbonyl}amino)phenyl]{2-[5-(tritylamino)-1H-pyrazol-1-yl]ethyl}carbamate

[2236]¹H-NMR(CDCl₃): δ 1.01(3H, d, J=6.2 Hz), 1.29(9H, s), 1.41(2H, qd,J=12.7, 4.3 Hz), 1.48-1.80(1H, m), 1.84(2H, br d, J=12.7 Hz), 2.65(3H,s), 3.00(2H, qd, J=12.4, 2.2 Hz), 3.33(2H, br d, J=12.7 Hz), 3.83(2H, t,J=7.8 Hz), 4.20(2H, t, J=7.8 Hz), 4.77(1H, d, J=2.4 Hz), 6.94(2H, d,J=8.6 Hz), 6.97(1H, d, J=2.4 Hz), 7.03(1H, d, J=7.8 Hz), 7.18-7.36(15H,m), 7.62(2H, d, J=8.9 Hz), 8.36(1H, d, J=8.4 Hz), 11.86(1H, s)ESI-MS(m/z): 798(M+Na)⁺

EXAMPLE 449

[2237] The following compound was obtained in substantially the samemanner as in Example 445.

[2238]N-(4-{[2-(5-Amino-1H-pyrazol-1-yl)ethyl]amino}phenyl)-6-methyl-2-(4-methyl-1-piperidinyl)nicotinamide

[2239]¹H-NMR(CDCl₃): δ 1.02(3H, d, J=6.2 Hz), 1.40(2H, qd, J=12.4, 3.8Hz), 1.48-1.85(1H, m), 1.83(2H, br d, J=12.7 Hz), 2.18(3H, s), 2.52(3H,s), 2.98(2H, td, J=12.2, 2.2 Hz), 3.34(2H, br d, J=12.4 Hz), 3.59(2H, t,J=5.7 Hz), 4.20(2H, t, J=5.1 Hz), 5.53(1H, d, J=1.9 Hz), 6.61(2H, d,J=8.9 Hz), 7.01(1H, d, J=8.1 Hz), 7.32(1H, d, J=1.9 Hz), 7.55(2H, d,J=8.6 Hz), 8.35(1H, d, J=7.6 Hz), 11.56(1H, br s) ESI-MS(m/z): 434(M+H)⁺

EXAMPLE 450

[2240] To a solution of 2-(4-methylphenyl)-1-cyclohexene-1-carboxylicacid (116 mg) in toluene (1.2 ml) were added thionyl chloride (0.078 ml)and N,N-dimethylformamide (1 drop) and the mixture was stirred at 80° C.for 1 hour. The mixture was evaporated in vacuo and the residue wasdissolved in tetrahydrofuran (1.0 ml). The acid chloride intetrahydrofuran was added to a solution of tert-butyl4-aminophenyl{2-[5-(tritylamino)-1H-pyrazol-1-yl)ethyl}carbamate (250mg) and triethylamine (0.093 ml) in tetrahydrofuran (1.5 ml) at ambienttemperature and the mixture was stirred at the same temperature for 2hours. The mixture was poured into water and extracted with ethylacetate. The organic layer was washed with brine, dried over magnesiumsulfate and evaporated in vacuo. The residue was recrystallized fromethyl acetate-hexane to give tert-butyl4-({[2-(4-methylphenyl)-1-cyclohexen-1-yl]carbonyl}amino)phenyl{2-[5-(tritylamino)-1H-pyrazol-1-yl]ethyl}carbamate(155.8 mg) as pale yellow powder.

[2241]¹H-NMR(CDCl₃): δ 1.26(9H, s), 1.77(4H, br s), 2.31(3H, s),2.42(2H, br s), 2.52(2H, br s), 3.74(2H, t, J=7.3 Hz), 4.08(2H, t, J=7.3Hz), 4.76(1H, d, J=1.6 Hz), 6.61(1H, br s), 6.73(2H, d, J=8.4 Hz),6.87(2H, d, J=8.9 Hz), 6.96(1H, d, J=2.2 Hz), 7.18-7.28(13H, m),7.32-7.36(6H, m) ESI-MS(m/z): 780(M+Na)⁺

EXAMPLE 451

[2242] The following compound was obtained in substantially the samemanner as in Example 445.

[2243]N-(4-{[2-(5-Amino-1H-pyrazol-1-yl)ethyl]amino}phenyl)-2-(4-methylphenyl)-1-cyclohexene-1-carboxamide

[2244]¹H-NMR(CDCl₃): δ 1.76(4H, br s), 2.33(3H, s), 2.41(2H, br s),2.51(2H, br s), 3.50(2H, t, J=5.4 Hz), 4.15(2H, t, J=5.4 Hz), 5.49(1H,d, J=1.9 Hz), 6.40(2H, d, J=8.6 Hz), 6.44(1H, s), 6.76(2H, d, J=8.9 Hz),7.12-7.19(4H, m), 7.28(1H, d, J=1.6 Hz) ESI-MS(m/z): 416(M+H)⁺

EXAMPLE 452

[2245] The following compound was obtained in substantially the samemanner as in Example 450.

[2246] tert-Butyl(4-{[(4′-methyl-1,1′-biphenyl-2-yl)carbonyl]amino}phenyl){2-[5-(tritylamino)-1H-pyrazol-1-yl]ethyl}carbamate

[2247]¹H-NMR(CDCl₃): δ 1.28(9H, s), 2.39(3H, s), 3.77(2H, t, J=7.0 Hz),4.11(2H, t, J=7.0 Hz), 4.77(1H, d, J=1.9 Hz), 6.79(2H, d, J=8.9 Hz),6.94(1H, br s), 6.96(1H, d, J=2.2 Hz), 7.02(2H, d, J=8.9 Hz),7.19-7.28(11H, m), 7.32-7.39(8H, m), 7.40-7.53(3H, m), 7.88(1H, dd,J=7.3, 1.1 Hz) ESI-MS(m/z): 776(M+Na)⁺

EXAMPLE 453

[2248] The following compound was obtained in substantially the samemanner as in Example 445.

[2249]N-(4-{[2-(5-Amino-1H-pyrazol-1-yl)ethyl]amino}phenyl)-4′-methyl-1,1′-biphenyl-2-carboxamide

[2250]¹H-NMR(CDCl₃): δ 2.40(3H, s), 3.52(2H, t, J=5.7 Hz), 4.14(2H, t,J=5.7 Hz), 5.51(1H, d, J=2.2 Hz), 6.45(2H, d, J=8.9 Hz), 6.77(1H, br s),6.92(2H, d, J=7.8 Hz), 7.24(2H, d, J=7.8 Hz), 7.29(1H, d, J=1.9 Hz),7.36(2H, d, J=6.2 Hz), 7.38(3H, m), 7.85(1H, dd, J=7.3, 1.1 Hz)ESI-MS(m/z): 412(M+H)⁺

[2251] Preparation 219

[2252] To a solution ofN-(1-(2-aminoethyl)-1H-pyrazol-5-yl)-N-tritylamine (1.853 g) inN,N-dimethylformamide (18.5 ml) was added to triethylamine (1.05 ml),followed by 2-chloro-5-nitropyridine (0.956 g) at ambient temperature.The mixture was stirred at 50° C. for 14 hours. The reaction mixture wascooled to ambient temperature, poured into water and extracted withethyl acetate. The organic layer was washed with brine, dried overmagnesium sulfate, filtered and concentrated in vacuo. The residue wasrecrystallized from ethyl acetate-hexane to give5-nitro-N-{2-[5-(tritylamino)-1H-pyrazol-1-yl]ethyl}-2-pyridinamine(2.23 g) as pale yellow powder.

[2253]¹H-NMR(CDCl₃): δ 3.73(2H, br q, J=6.2 Hz), 4.13(2H, t, J=6.5 Hz),4.85(1H, d, J=1.9 Hz), 4.90(1H, br s), 5.80(1H, br t, J=5.7 Hz),6.32(1H, d, J=9.5 Hz), 7.06(1H, d, J=2.2 Hz), 7.20-7.26(15H, m),8.07(1H, dd, J=9.5, 2.7 Hz), 8.49(1H, d, J=2.4 Hz) ESI-MS(m/z):513(M+Na)⁺

[2254] Preparation 220

[2255] To a solution of5-nitro-N-{2-[5-(tritylamino)-1H-pyrazol-1-yl]ethyl}-2-pyridinamine(2.22 g) and 4-(N,N-dimethylamino)pyridine (55.3 mg) in tetrahydrofuran(22 ml) was added di-t-butyl dicarbonate (1.48 g). The mixture wasstirred at 40° C. for 1.4 hours. The reaction mixture was cooled toambient temperature and concentrated in vacuo. The residue was dissolvedin ethyl acetate and water, and extracted with ethyl acetate. Theorganic layer was washed with brine, dried over magnesium sulfate,filtered and concentrated in vacuo. The residue was recrystallized fromethyl acetate-hexane to give tert-butyl5-nitro-2-pyridinyl{2-[5-(tritylamino)-1H-pyrazol-1-yl]ethyl}carbamate(2.54 g) as dark yellow powder.

[2256]¹H-NMR(CDCl₃): δ 1.52(9H, s), 4.19-4.38(4H, m), 4.76(1H, d, J=1.9Hz), 5.21(1H, s), 7.01(1H, d, J=2.2 Hz), 7.20-7.35(15H, m),8.12-8.16(1H, m), 8.25-8.30(2H, m) ESI-MS(m/z): 613(M+Na)⁺

[2257] Preparation 221

[2258] A solution of tert-butyl5-nitro-2-pyridinyl{2-[5-(tritylamino)-1H-pyrazol-1-yl]ethyl}carbamate(2.49 g) in methanol (25 ml) was hydrogenated over 10% palladium oncarbon (0.50 g, 50% wet) at ambient temperature under atmosphericpressure of hydrogen for 2.5 hours. The reaction mixture was filteredthrough a short pad of celite, and the filtrate was concentrated invacuo to give tert-butyl5-amino-2-pyridinyl{2-[5-(tritylamino)-1H-pyrazol-1-yl]ethyl}carbamate(2.23 g) as a pale yellow foam.

[2259]¹H-NMR(CDCl₃): δ 1.40(9H, s), 3.36(2H, br s), 3.93(2H, t, J=7.6Hz), 4.32(2H, t, J=7.3 Hz), 4.77(1H, d, J=2.2 Hz), 6.91(1H, dd, J=8.9,3.0 Hz), 7.00(1H, d, J=1.9 Hz), 7.17-7.43(17H, m) ESI-MS (m/z):583(M+Na)⁺

EXAMPLE 454

[2260] To a solution of tert-butyl5-amino-2-pyridinyl{2-[5-(tritylamino)-1H-pyrazol-1-yl]ethyl}carbamate(350 mg), 4-chloro-2-(dimethylamino)benzoic acid (137 mg) and1-hydroxybenzotriazole (105 mg) in N,N-dimethylformamide (3.5 ml) wasadded 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (132mg), followed by triethylamine (0.1 ml) at ambient temperature. Thereaction mixture was stirred for 16 hours at 60° C. and concentrated invacuo. The residue was dissolved in ethyl acetate and water andextracted with ethyl acetate. The organic layer was washed with waterand brine, dried over magnesium sulfate, filtered and concentrated invacuo. The residue was purified by column chromatography on silica geleluting with hexane: ethyl acetate (3:1→1:1) to give tert-butyl5-{[4-chloro-2-(dimethylamino)benzoyl]amino}-2-pyridinyl{2-[5-(tritylamino)-1H-pyrazol-1-yl]ethyl}carbamate(299.5 mg) as a yellow foam.

[2261]¹H-NMR(CDCl₃): δ 1.42(9H, s), 2.83(6H, s), 4.07(2H, t, J=6.2 Hz),4.31(2H, t, J=6.2 Hz), 4.77(1H, d, J=1.9 Hz), 5.81(1H, s), 7.01(1H, d,J=2.2 Hz), 7.17-7.39(17H, m), 7.56(1H, d, J=8.9 Hz), 7.63(1H, br d,J=2.7 Hz), 8.16(1H, dd, J=8.1, 1.1 Hz), 8.29(1H, dd, J=8.9, 3.0 Hz),11.54(1H, s) ESI-MS(m/z): 743(M+H)⁺

EXAMPLE 455

[2262] To a solution of tert-butyl5-{[4-chloro-2-(dimethylamino)benzoyl]amino}-2-pyridinyl{2-[5-(tritylamino)-1H-pyrazol-1-yl]ethyl}carbamate(293.6 mg) in dichloromethane (3 ml) was added trifluoroacetic acid(0.914 ml). The reaction mixture was stirred for 12 hours, quenched with10% potassium carbonate solution and extracted with dichloromethane. Theorganic layer was washed with brine, dried over magnesium sulfate,filtered and concentrated in vacuo. The residue was recrystallized fromethyl acetate-hexane to giveN-(6-{[2-(5-amino-1H-pyrazol-1-yl)ethyl]amino}-3-pyridinyl)-4-chloro-2-(dimethylamino)benzamide(73.7 mg) as pale yellow green powder.

[2263]¹H-NMR(CDCl₃): δ 2.83(6H, s), 3.72(2H, br q, J=5.9 Hz), 4.02(2H,br s), 4.22(2H, t, J=6.5 Hz), 4.80(1H, br t, J=5.9 Hz), 5.51(1H, d,J=1.6 Hz), 6.44(1H, d, J=8.9 Hz), 7.23(1H, d, J=1.9 Hz), 7.26-7.29(2H,m), 7.93(1H, dd, J=8.9, 2.7 Hz), 8.16(1H, dd, J=7.8, 0.5 Hz), 8.23(1H,d, J=2.4 Hz), 11.59(1H, s) ESI-MS(m/z): 400(M+H)⁺

EXAMPLE 456

[2264] To a solution of 2-(4-methylphenyl)-1-cyclohexene-1-carboxylicacid (127 mg) in toluene (1.3 ml) were added thionyl chloride (0.086 ml)and N,N-dimethylformamide (1 drop) and the mixture was stirred at 80° C.for 1 hour. The mixture was evaporated in vacuo and the residue wasdissolved in tetrahydrofuran (1.0 ml). The acid chloride intetrahydrofuran was added to a solution of tert-butyl5-amino-2-pyridinyl{2-[5-(tritylamino)-1H-pyrazol-1-yl]ethyl}carbamate(300 mg) and triethylamine (0.09 mL) in tetrahydrofuran (2.0 ml) atambient temperature and the mixture was stirred at the same temperaturefor 15 hours. The mixture was poured into water and extracted with ethylacetate. The organic layer was washed with brine, dried over magnesiumsulfate and evaporated in vacuo. The residue was purified by columnchromatography on silica gel eluting with hexane: ethyl acetate(3:1→1:1) to give tert-butyl5-({[2-(4-methylphenyl)-1-cyclohexen-1-yl]carbonyl}amino)-2-pyridinyl{2-[5-(tritylamino)-1H-pyrazol-1-yl]ethyl}carbamate(334.4 mg).

[2265]¹H-NMR(CDCl₃): δ 1.41(9H, s), 1.79(4H, br s), 2.32(3H, s),2.45(2H, br s), 2.53(2H, br s), 3.96(2H, t, J=7.0 Hz), 4.23(2H, t, J=6.5Hz), 4.75(1H, d, J=1.9 Hz), 5.75(1H, s), 6.81(1H, br d, J=2.7 Hz),7.11-7.35(19H, m), 7.42(1H, d, J=8.9 Hz), 7.68(1H, dd, J=9.2, 2.7 Hz)ESI-MS(m/z): 781(M+Na)⁺

EXAMPLE 457

[2266] The following compound was obtained in substantially the samemanner as in Example 455.

[2267]N-(6-{[2-(5-Amino-1H-pyrazol-1-yl)ethyl]amino}-3-pyridinyl)-2-(4-methylphenyl)-1-cyclohexene-1-carboxamide

[2268]¹H-NMR(CDCl₃): δ 1.76(4H, br s), 2.34(3H, s), 2.41(2H, br s),2.51(2H, br s), 3.63(2H, q, J=5.9 Hz), 3.93(2H, br s), 4.13(2H, t, J=6.5Hz), 4.71(1H, br t, J=5.9 Hz), 5.46(1H, d, J=1.9 Hz), 6.23(1H, d, J=8.9Hz), 6.40(1H, s), 7.05-7.10(4H, m), 7.21-7.33(2H, m), 7.48(1H, d, J=2.2Hz) ESI-MS(m/z): 417(M+H)⁺

EXAMPLE 458

[2269] The following compound was obtained in substantially the samemanner as in Example 454.

[2270] tert-Butyl[5-({[6-methyl-2-(4-methyl-1-piperidinyl)-3-pyridinyl]carbonyl}amino)-2-pyridinyl]{2-[5-(tritylamino)-1H-pyrazol-1-yl]ethyl}carbamate

[2271]¹H-NMR(CDCl₃): δ 1.03(3H, d, J=6.5 Hz), 1.20-1.40(2H, m), 1.43(9H,s), 1.58-1.70(1H, m), 1.85(2H, br d, J=13.5 Hz), 2.55(3H, s), 3.02(2H,td, J=12.2, 2.4 Hz), 3.33(2H, br d, J=12.4 Hz), 4.09(2H, t, J=7.6 Hz),4.30(2H, t, J=6.8 Hz), 4.79(1H, d, J=2.2 Hz), 5.66(1H, s), 7.01(1H, d,J=2.2 Hz), 7.06(1H, d, J=7.8 Hz), 7.12-7.41(15H, m), 7.57(1H, d, J=8.9Hz), 7.86(1H, d, J=2.2 Hz), 8.27(1H, dd, J=9.2, 3.0 Hz), 8.37(1H, d,J=7.8 Hz), 11.76(1H, s) ESI-MS(m/z): 799(M+Na)⁺

EXAMPLE 459

[2272] The following compound was obtained in substantially the samemanner as in Example 455.

[2273]N-(6-{[2-(5-Amino-1H-pyrazol-1-yl)ethyl]amino}-3-pyridinyl)-6-methyl-2-(4-methyl-1-piperidinyl)nicotinamide

[2274]¹H-NMR(CDCl₃): δ 1.03(3H, d, J=6.8 Hz), 1.38(2H, qd, J=12.4, 3.2Hz), 1.55-1.68(1H, m), 1.86(2H, br d, J=12.7 Hz), 2.52(3H, s), 3.01(2H,td, J=12.2, 2.2 Hz), 3.32(2H, d, J=12.4 Hz), 3.73(2H, q, J=5.9 Hz),3.96(2H, br s), 4.22(2H, t, J=6.2 Hz), 4.82(1H, t, J=5.9 Hz), 5.50(1H,d, J=1.9 Hz), 6.46(1H, d, J=8.9 Hz), 7.03(1H, d, J=7.8 Hz), 7.28(1H, d,J=1.9 Hz), 7.98(1H, dd, J=8.9, 2.7 Hz), 8.33(1H, d, J=3.0 Hz), 8.35(1H,d, J=7.8 Hz), 11.75(1H, s) ESI-MS(m/z): 435(M+H)⁺

EXAMPLE 460

[2275] The following compound was obtained in substantially the samemanner as in Example 456.

[2276] tert-Butyl(5-{[(4′-methyl-1,1′-biphenyl-2-yl)carbonyl]amino}-2-pyridinyl){2-[5-(tritylamino)-1H-pyrazol-1-yl]ethyl}carbamate

[2277]¹H-NMR(CDCl₃): δ 1.43(9H, s), 2.39(3H, s), 3.99(2H, t, J=7.8 Hz),4.27(2H, t, J=7.6 Hz), 4.76(1H, d, J=1.9 Hz), 5.79(1H, br s), 6.69(1H,br s), 6.98(1H, d, J=1.9 Hz), 7.13-7.59(24H, m), 7.84(2H, d, J=8.9 Hz)ESI-MS (m/z): 777 (M+Na)⁺

EXAMPLE 461

[2278] The following compound was obtained in substantially the samemanner as in Example 455.

[2279]N-(6-{[2-(5-Amino-1H-pyrazol-1-yl)ethyl]amino}-3-pyridinyl)-4′-methyl-1,1′-biphenyl-2-carboxamide

[2280]¹H-NMR(CDCl₃): δ 2.41(3H, s), 3.65(2H, q, J=6.2 Hz), 3.94(2H, brs), 4.15(2H, t, J=6.2 Hz), 4.79(1H, br t, J=5.9 Hz), 5.48(1H, d, J=1.9Hz), 6.31(1H, d, J=8.9 Hz), 6.73(1H, s), 7.24-7.27(3H, m), 7.36(2H, d,J=7.8 Hz), 7.37-7.53(4H, m), 7.64(1H, d, J=2.2 Hz), 7.85(1H, dd, J=7.3,1.4 Hz) ESI-MS(m/z): 413(M+H)⁺

EXAMPLE 462

[2281] The following compound was obtained in substantially the samemanner as in Example 454.

[2282] tert-Butyl(4-([2-(dimethylamino)-4-(trifluoromethyl)benzoyl]amino}phenyl){2-[5-(tritylamino)-1H-pyrazol-1-yl]ethyl}carbamate

[2283]¹H-NMR(CDCl₃): δ 1.28(9H, s), 2.87(6H, s), 3.83(2H, t, J=7.0 Hz),4.27(2H, t, J=7.0 Hz), 4.76(1H, d, J=1.9 Hz), 6.94(2H, d, J=8.6 Hz),6.97(1H, d, J=2.2 Hz), 7.19-7.42(15H, m), 7.48-7.50(2H, m), 7.55(2H, d,J=8.9 Hz), 8.32(1H, d, J=8.6 Hz), 11.67(1H, s) ESI-MS(m/z): 797(M+Na)⁺

EXAMPLE 463

[2284] The following compound was obtained in substantially the samemanner as in Example 455.

[2285]N-(4-{[2-(5-Amino-1H-pyrazol-1-yl)ethyl]amino}phenyl)-2-(dimethylamino)-4-(trifluoromethyl)benzamide

[2286]¹H-NMR(CDCl₃): δ 2.86(3H, s), 3.49(2H, br s), 3.57(2H, t, J=5.7Hz), 4.20(2H, t, J=5.7 Hz), 5.53(1H, d, J=1.9 Hz), 6.60(2H, d, J=8.9Hz), 7.32(1H, d, J=2.2 Hz), 7.46-7.49(4H, m), 7.30(1H, d, J=8.4 Hz),11.31(1H, br s) ESI-MS (m/z): 433 (M+H)⁺

EXAMPLE 464

[2287] To a solution of6-{2-[5-(tritylamino)-1H-pyrazol-1-yl]ethoxy}-3-pyridinamine (320 mg),4-chloro-2-(dimethylamino)benzoic acid (152 mg) and1-hydroxybenzotriazole hydrate (127 mg) in N,N-dimethylformamide (5 ml)were added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride(159 mg) and triethylamine (0.145 ml)at ambient temperature. Thereaction mixture was stirred for 13 hours at 50° C. and concentrated invacuo. The residue was dissolved in ethyl acetate and water andextracted with ethyl acetate. The organic layer was washed with waterand brine, dried over magnesium sulfate, filtered and concentrated invacuo. The residue was recrystallized from ethyl acetate-diisopropylether to give4-chloro-2-(dimethylamino)-N-(6-{2-[5-(tritylamino)-1H-pyrazol-1-yl]ethoxy}-3-pyridinyl)benzamide(382 mg) as a pale yellow solid.

[2288]¹H-NMR(CDCl₃): δ 2.81(3H, s), 4.44(2H, t, J=4.7 Hz), 4.58(2H, t,J=4.7 Hz), 4.62(1H, d, J=2.0 Hz), 5.90(1H, s), 6.00(1H, d, J=8.9 Hz),7.01(1H, d, J=2.0 Hz), 7.23-7.33(17H, m), 7.96(1H, d, J=2.6 Hz),8.04(1H, dd, J=8.9, 2.6 Hz), 11.73(1H, s) ESI-MS(m/z): 665(M+Na)⁺

EXAMPLE 465

[2289] To a solution of4-chloro-2-(dimethylamino)-N-(6-{2-[5-(tritylamino)-1H-pyrazol-1-yl]ethoxy}-3-pyridinyl)benzamide(370 mg) in methanol (6 ml) was added concentrated hydrochloric acid(600 mg). The reaction mixture was stirred for 14 hours at ambienttemperature, quenched with 10% potassium carbonate solution, andextracted with ethyl acetate. The organic layer was washed with brine,dried over magnesium sulfate, filtered and concentrated in vacuo. Theresidue was recrystallized from ethyl acetate-diisopropyl ether to giveN-{6-[2-(5-amino-1H-pyrazol-1-yl)ethoxy]-3-pyridinyl}-4-chloro-2-(dimethylamino)benzamide(178 mg) as pale brown solids.

[2290]¹H-NMR(DMSO-d₆): δ 2.79(6H, s), 4.22(2H, t, J=6.0 Hz), 4.48(2H, t,J=6.0 Hz), 5.17(2H, s), 5.27(1H, d, J=1.6 Hz), 6.82(1H, d, J=8.9 Hz),7.00(1H, dd, J=8.2, 2.0 Hz), 7.05(1H, d, J=2.0 Hz), 7.08(1H, d, J=2.0Hz), 7.52(1H, d, J=8.2 Hz), 8.01(1H, dd, J=8.9, 2.0 Hz), 8.47(1H, d,J=2.0 Hz), 10.71(1H, s) ESI-MS(m/z): 423(M+Na)⁺

EXAMPLE 466

[2291] To a solution of tert-butyl5-amino-2-pyridinyl[2-(1H-pyrazol-1-yl)ethyl]carbamate (364 mg),4-chloro-2-(dimethylamino)benzoic acid (263 mg) and1-hydroxybenzotriazole hydrate (221 mg) in N,N-dimethylformamide (10 ml)were added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride(276 mg) and triethylamine (0.145 ml) at ambient temperature. Thereaction mixture was stirred for 13 hours at 50° C. and concentrated invacuo. The residue was dissolved in ethyl acetate and water, andextracted with ethyl acetate. The organic layer was washed with waterand brine, dried over magnesium sulfate, filtered and concentrated invacuo. The residue was recrystallized from ethyl acetate-diisopropylether to give tert-butyl5-{[4-chloro-2-(dimethylamino)benzoyl]amino}-2-pyridinyl[2-(1H-pyrazol-1-yl)ethyl]carbamate(357 mg) as a pale yellow solid.

[2292]¹H-NMR(CDCl₃): δ 1.46(9H, s), 2.84(6H, s), 4.30-4.35(2H, m),4.42-4.46(2H, m), 6.20(1H, t, J=2.0 Hz), 7.25-7.29(4H, m), 7.37(1H, dd,J=1.6, 0.6 Hz), 7.46(1H, dd, J=1.6, 0.6 Hz), 7.49(1H, d, J=9.2 Hz),8.17-8.21(2H, m), 8.45(1H, d, J=2.3 Hz), 12.02(1H, s) ESI-MS(m/z):507(M+Na)⁺

EXAMPLE 467

[2293] To a solution of tert-butyl5-{[4-chloro-2-(dimethylamino)benzoyl]amino}-2-pyridinyl[2-(1H-pyrazol-1-yl)ethyl]carbamate(347 mg) in dichloromethane (10 ml) was added trifluoroacetic acid(0.674 ml). The reaction mixture was stirred for 20 hours at ambienttemperature, quenched with 10% potassium carbonate solution andextracted with dichloromethane. The organic layer was washed with brine,dried over magnesium sulfate, filtered and concentrated in vacuo. Theresidue was recrystallized from ethyl acetate-diisopropyl ether to give4-chloro-2-(dimethylamino)-N-(6-{[2-(1H-pyrazol-1-yl)ethyl]amino}-3-pyridinyl)benzamide(243 mg) as a pale yellow solid.

[2294]¹H-NMR(DMSO-d₆): δ 2.80(6H, s), 3.61(2H, q, J=6.3 Hz), 4.27(2H, t,J=6.3 Hz), 6.22(1H, t, J=2.3 Hz), 6.48(1H, d, J=8.6 Hz), 6.56(1H, t,J=5.7 Hz), 7.00(1H, dd, J=2.3, 0.6 Hz), 7.08(1H, d, J=2.0 Hz), 7.45(1H,dd, J=2.0, 0.6 Hz), 7.52(1H, d, J=8.2 Hz), 7.07(1H, dd, J=2.3, 0.6 Hz),7.71(1H, dd, J=8.9, 2.6 Hz), 8.28(1H, d, J=2.6 Hz), 10.45(1H, s)ESI-MS(m/z): 385(M+H)⁺

EXAMPLE 468

[2295] To a solution of tert-butyl4-aminophenyl[2-(1H-pyrazol-1-yl)ethyl]carbamate (346 mg),2-(dimethylamino)-4-(trifluoromethyl)benzoic acid (294 mg) and1-hydroxybenzotriazole (193 mg) in N,N-dimethylformamide (3.5 ml) wasadded 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (241mg), followed by triethylamine (0.24 ml) at ambient temperature. Thereaction mixture was stirred for 15 hours at 60° C. and concentrated invacuo. The residue was dissolved in ethyl acetate and water, andextracted with ethyl acetate. The organic layer was washed with waterand brine, dried over magnesium sulfate, filtered and concentrated invacuo. The residue was purified by column chromatography on silica geleluting with hexane: ethyl acetate (3:1) to give tert-butyl4-{[2-(dimethylamino)-4-(trifluoromethyl)benzoyl]amino}phenyl[2-(1H-pyrazol-1-yl)ethyl]carbamate(440 mg) as pale yellow oil.

[2296]¹H-NMR(CDCl₃): δ 1.41(9H, s), 2.87(6H, s), 4.04(2H, t, J=5.9 Hz),4.38(2H, t, J=5.9 Hz), 6.26(1H, t, J=1.9 Hz), 6.90-7.05(2H, m),7.40-7.50(3H, m), 7.57(2H, d, J=8.6 Hz), 8.31(1H, dd, J=8.6, 0.5 Hz),11.64(1H, s) ESI-MS (m/z): 540 (M+Na)⁺

EXAMPLE 469

[2297] To a solution of tert-butyl4-{[2-(dimethylamino)-4-(trifluoromethyl)benzoyl]amino}phenyl[2-(1H-pyrazol-1-yl)ethyl]carbamate (430 mg) in dichloromethane (3 ml)was added trifluoroacetic acid (0.96 ml). The reaction mixture wasstirred for 14 hours, quenched with 10% potassium carbonate solution andextracted with dichloromethane. The organic layer was washed with brine,dried over magnesium sulfate, filtered and concentrated in vacuo. Theresidue was recrystallized from ethyl acetate-hexane to give2-(dimethylamino)-N-(4-{([2-(1H-pyrazol-1-yl)ethyl]amino}phenyl)-4-(trifluoromethyl)benzamide (334 mg) as whitepowder.

[2298]¹H-NMR (CDCl₃): δ 2.86 (6H, s), 3.61 (2H, t, J=5.1 Hz), 4.03 (1H,br s), 4.36(2H, t, J=5.4 Hz), 6.26(1H, br s), 6.62(2H, d, J=8.6 Hz),7.36-7.56(4H, m), 8.30(1H, d, J=8.1 Hz), 11.27(1H, br s) ESI-MS(m/z):418(M+H)⁺

EXAMPLE 470

[2299] The following compound was obtained in substantially the samemanner as in Example 468.

[2300] tert-Butyl (4-{[4-methyl-2-(methylamino)benzoyl]amino}phenyl)[2-(1H-pyrazol-1-yl)ethyl]carbamate

[2301]¹H-NMR(CDCl₃): δ 1.39 (9H, s), 2.36 (3H, s), 2.87 (3H, s), 3.40(1H, br q, J=6.2 Hz), 4.01(2H, t, J=5.9 Hz), 4.35(2H, t, J=6.2 Hz),6.25(1H, t, J=2.2 Hz), 6.38-6.50(4H, m), 7.34-7.49(4H, m), 7.83(1H, brs) ESI-MS (m/z): 472 (M+Na)⁺

EXAMPLE 471

[2302] The following compound was obtained in substantially the samemanner as in Example 469.

[2303]4-Methyl-2-(methylamino)-N-(4-{[2-(1H-pyrazol-1-yl)ethyl]amino}phenyl)benzamide

[2304]¹H-NMR(CDCl₃): δ 2.34 (3H, s), 2.85 (3H, br s), 3.59 (2H, t, J=5.7Hz), 4.34(2H, t, J=5.4 Hz), 6.25(1H, t, J=2.4 Hz), 6.45(1H, d, J=7.8Hz), 6.49(1H, br s), 6.59(2H, d, J=8.6 Hz), 7.31(2H, d, J=8.6 Hz),7.34(1H, d, J=7.8 Hz), 7.35(1H, d, J=2.2 Hz), 7.48(1H, br s), 7.54(1H,br s), 7.55(1H, d, J=1.9 Hz) ESI-MS(m/z): 350(M+H)⁺

EXAMPLE 472

[2305] The following compound was obtained in substantially the samemanner as in Example 468.

[2306] tert-Butyl(4-{[2-(dimethylamino)-4-ethylbenzoyl]amino}phenyl)[2-(1H-pyrazol-1-yl)ethyl]carbamate

[2307]¹H-NMR(CDCl₃): δ 1.27(3H, t, J=7.6 Hz), 1.41(9H, s), 2.70(2H, q,J=7.6 Hz), 2.82(6H, s), 4.03(2H, t, J=6.2 Hz), 4.36(2H, t, J=5.7 Hz),6.25(1H, t, J=1.9 Hz), 6.90-7.01(2H, m), 7.11(1H, d, J=6.2 Hz), 7.12(1H,s), 7.40(1H, d, J=1.9 Hz), 7.50(1H, d, J=0.8 Hz), 7.59(2H, d, J=8.6 Hz),8.18(1H, s, J=8.4 Hz), 12.29(1H, s) ESI-MS(m/z): 500(M+Na)⁺

EXAMPLE 473

[2308] The following compound was obtained in substantially the samemanner as in Example 469.

[2309]2-(Dimethylamino)-4-ethyl-N-(4-{[2-(1H-pyrazol-1-yl)ethyl]amino}phenyl)benzamide

[2310]¹H-NMR(CDCl₃): δ 1.26(3H, t, J=7.8 Hz), 2.68(2H, q, J=7.8 Hz),2.81(6H, s), 3.60(2H, t, J=5.1 Hz), 3.95(1H, br s), 4.35(2H, t, J=5.4Hz), 6.25(1H, t, J=1.9 Hz), 6.61(2H, d, J=8.6 Hz), 7.09(2H, br s),7.36(1H, d, J=1.9 Hz), 7.49(2H, d, J=8.4 Hz), 7.56(1H, d, J=1.9 Hz),8.17(1H, d, J=8.4 Hz), 11.89(1H, br s) ESI-MS(m/z): 378(M+H)⁺

EXAMPLE 474

[2311] The following compound was obtained in substantially the samemanner as in Example 468.

[2312] tert-Butyl(4-{[2-(dimethylamino)-4-fluorobenzoyl]amino}phenyl)[2-(1H-pyrazol-1-yl)ethyl]carbamate

[2313]¹H-NMR(CDCl₃): δ 1.40(9H, s), 2.81(6H, s), 4.03(2H, t, J=6.2 Hz),4.37(2H, t, J=5.4 Hz), 6.25(1H, t, J=1.9 Hz), 6.86-6.99(2H, m),7.26-7.56(3H, m), 7.70-7.79(3H, m), 8.17-8.24(1H, m), 11.64(1H, br s)ESI-MS(m/z): 490(M+Na)⁺

EXAMPLE 475

[2314] The following compound was obtained in substantially the samemanner as in Example 469.

[2315]2-(Dimethylamino)-4-fluoro-N-(4-{[2-(1H-pyrazol-1-yl)ethyl]amino}phenyl)benzamide

[2316]¹H-NMR(CDCl₃): δ 2.81(6H, s), 3.60(2H, t, J=5.4 Hz), 3.99(1H, brs), 4.35(2H, t, J=5.7 Hz), 6.25(1H, t, J=1.9 Hz), 6.61(2H, d, J=8.4 Hz),6.86-6.96(2H, m), 7.36(1H, d, J=2.2 Hz), 7.47(2H, d, J=8.6 Hz), 7.56(1H,d, J=1.4 Hz), 8.17-8.24(1H, m), 11.24(1H, s) ESI-MS(m/z): 368(M+H)⁺

[2317] This application is based on applications Nos. 2002952331 and2003902622, both of which were filed in Australia, and the contents ofwhich are incorporated hereinto by reference.

1. A compound of the formula (I)

wherein R¹ is hydrogen, lower alkyl, lower alkenyl, halo(lower)alkyl,cyclo(lower)alkyl, lower alkoxy, lower alkylthio, acyl, optionallysubstituted aryl or NR³R⁴, wherein R³ and R⁴ are each independentlyhydrogen, lower alkyl, cyclo(lower)alkyl or acyl; or R³, R⁴ and nitrogenatom to which they are attached form an optionally substituted,saturated or partially saturated N-containing heterocyclic groupoptionally having one or more oxygen or sulfur atom(s) and optionallyhaving one or two lower alkyl(s); R² is hydrogen; or aryl or heteroarylin which imino group is optionally protected by amino protective group,each of which is optionally substituted by cyano, optionally protectedamino, lower alkyl or heteroaryl substituted by one or more loweralkyl(s); X is direct bond or bivalent residue derived from piperazine;Y is -(A¹)_(n)-(A²)_(m)- wherein A¹ is —O—, —NH—, —N(R⁵)—, —CO—,—CH(OH)—, —NH—CO—, —CO—NH—, —CH₂—NH—CO—, —CH₂—CO—NH— or —(CH₂)₂—NH—CO—,wherein R⁵ is amino protective group, A² is lower alkylene optionallysubstituted with lower alkyl or heteroaryl, and n and m areindependently 0 or 1;

is bivalent residue derived from arene or heteroarene; and

is bivalent residue derived from arene or heteroarene selected from

wherein Z is N or C(R¹⁰) R⁶ is hydrogen, halogen, lower alkyl, loweralkoxy, halo(lower)alkyl, lower alkanoyl, lower alkylthio or —NR⁸R⁹,wherein R⁸ and R⁹ are each independently lower alkyl, or R⁸, R⁹ andnitrogen atom to which they are attached form an optionally substituted,saturated or partially saturated N-containing heterocyclic groupoptionally having one or two lower alkyl(s); R⁷ is lower alkyl; R¹⁰ isthe same as R⁶ defined above; and q is 1 or 2, or a salt thereof.
 2. Thecompound of claim 1, wherein R¹ is hydrogen, lower alkyl, lower alkenyl,halo(lower)alkyl, cyclo(lower)alkyl, lower alkoxy, lower alkylthio,lower alkylsulfonyl or NR³R⁴, wherein R³ and R⁴ are each independentlyhydrogen, lower alkyl, cyclo(lower)alkyl, lower alkanoyl; or R³, R⁴ andnitrogen atom to which they are attached form an optionally substituted,saturated or partially saturated N-containing heterocyclic groupselected from

wherein R¹¹ and R¹² are each independently hydrogen or lower alkyl, andQ is —N(R¹³)—, —O—, —S—, —SO— or —SO₂—, wherein R¹³ is hydrogen or loweralkyl; R² is hydrogen, phenyl, pyridinyl, pyrimidinyl, pyrazolyl,thiazolyl, pyrrolyl, triazolyl in which imino group is optionallyprotected by amino protective group, tetrazolyl, furanyl or thienyl,each of which is optionally substituted by cyano, optionally protectedamino, lower alkyl or pyrrolyl substituted by one or more loweralkyl(s);

is phenylene, pyridinediyl, indolinediyl, isoindolynediyl,3-oxo-2,3-dihydro-1H-indolediyl or 3,4-dihydro-2(1H)-isoquinolinediyl;and

is bivalent residue derived from arene or heteroarene selected from

wherein Z is N or C(R¹⁰) R⁶ is hydrogen, halogen, lower alkyl, loweralkoxy, halo(lower)alkyl, lower alkanoyl, lower alkylthio or —NR⁸R⁹,wherein R⁸ and R⁹ are each independently lower alkyl, or R⁸, R⁹ andnitrogen atom to which they are attached form an optionally substituted,saturated or partially saturated N-containing heterocyclic groupselected from

wherein R¹¹, R¹² and Q are as defined above; R⁷ is as defined above; andq is 1 or 2, or a salt thereof.
 3. A compound of the formula (I′)

wherein R² is aryl or heteroaryl, each of which is optionallysubstituted by cyano, optionally protected amino, lower alkyl orheteroaryl substituted by one or more lower alkyl(s); R³ and R⁴ are eachindependently lower alkyl, or R³, R⁴ and nitrogen atom to which they areattached form an optionally substituted, saturated or partiallysaturated N-containing heterocyclic group; R⁶ is hydrogen, halogen,lower alkyl, lower alkoxy, halo(lower)alkyl, lower alkanoyl or —NR⁸R⁹(wherein R⁸ and R⁹ are each independently lower alkyl, or R⁸, R⁹ andnitrogen atom to which they are attached form an optionally substituted,saturated or partially saturated N-containing heterocyclic group);

is bivalent residue derived from arene or heteroarene; X is direct bondor bivalent residue derived from piperazine, Y is -(A¹)_(n)-(A²)_(m)-wherein A¹ is —O—, —NH—, —N(R⁵)—, —CO—, —CH(OH)—, —NH—CO—, —CH₂—NH—CO—or —CH₂—CO—NH—, wherein R⁵ is amino protective group, A² is loweralkylene, and n and m are independently 0 or 1; Z is N or C(R¹⁰)(wherein R¹⁰ is the same as R⁶ defined above), or a salt thereof.
 4. Thecompound of claim 3, wherein R² is phenyl, pyridinyl, pyrimidinyl,pyrazolyl, thiazolyl, pyrrolyl, triazolyl or tetrazolyl, each of whichis optionally substituted by cyano, optionally protected amino, loweralkyl or pyrrolyl substituted by one or more lower alkyl(s), R³ and R⁴are each independently lower alkyl, or R³, R⁴ and nitrogen atom to whichthey are attached form a saturated or partially saturated N-containingheterocyclic group selected from

wherein R¹¹ and R¹² are each independently hydrogen or lower alkyl, andQ is —N(R¹³)—, —O—, —S—, —SO— or —SO₂— wherein R¹³ is hydrogen or loweralkyl; R⁶ is hydrogen, halogen, lower alkyl, lower alkoxy,halo(lower)alkyl, lower alkanoyl or —NR⁸R⁹ (wherein R⁸ and R⁹ are eachindependently lower alkyl, or R¹¹, R¹² and nitrogen atom to which theyare attached form a saturated or partially saturated N-containingheterocyclic group selected from

wherein R¹¹, R¹² and Q are as defined above); and

is phenylene, pyridinediyl, indolinediyl or isoindolinediyl, or a saltthereof.
 5. The compound of claim 3, wherein R² is phenyl, pyridinyl,pyrimidinyl, pyrazolyl, thiazolyl, pyrrolyl, triazolyl or tetrazolyl,each of which is optionally substituted by cyano, optionally protectedamino, lower alkyl or pyrrolyl substituted by one or more loweralkyl(s); R³ and R⁴ are each independently lower alkyl; R⁶ is hydrogen,halogen, lower alkyl, lower alkoxy, lower alkanoyl or halo(lower)alkyl;and

is phenylene, or a salt thereof.
 6. The compound of claim 3, wherein R²is phenyl, pyridinyl, pyrimidinyl, pyrazolyl, thiazolyl, pyrrolyl,triazolyl or tetrazolyl, each of which is optionally substituted bycyano, optionally protected amino, lower alkyl or pyrrolyl substitutedby one or more lower alkyl(s); R³ and R⁴ are each independently loweralkyl; R⁶ is hydrogen, halogen, lower alkyl, lower alkoxy, loweralkanoyl or halo(lower)alkyl; and

is indolinediyl or isoindolinediyl, or a salt thereof.
 7. The compoundof claim 3, wherein R² is phenyl, pyridinyl, pyrimidinyl, pyrazolyl,thiazolyl, pyrrolyl, triazolyl or tetrazolyl, each of which isoptionally substituted by cyano, optionally protected amino, lower alkylor pyrrolyl substituted by one or more lower alkyl(s); R³, R⁴ andnitrogen atom to which they are attached form a saturated N-containingheterocyclic group of the formula

wherein R¹¹ and R¹² are each independently hydrogen or lower alkyl; R⁶is hydrogen, halogen, lower alkyl, lower alkoxy, lower alkanoyl orhalo(lower)alkyl; and

is phenylene, or a salt thereof.
 8. The compound of claim 3, wherein R²is phenyl, pyridinyl, pyrimidinyl, pyrazolyl, thiazolyl, pyrrolyl,triazolyl or tetrazolyl, each of which is optionally substituted bycyano, optionally protected amino, lower alkyl or pyrrolyl substitutedby one or more lower alkyl(s); R³, R⁴ and nitrogen atom to which theyare attached form a saturated N-containing heterocyclic group of theformula

wherein R¹¹ and R¹² are each independently hydrogen or lower alkyl; R⁶is hydrogen, halogen, lower alkyl, lower alkoxy, lower alkanoyl orhalo(lower)alkyl; and

is indolinediyl or isoindolinediyl, or a salt thereof.
 9. A compound ofthe formula (I″)

wherein R² is aryl or heteroaryl, each of which is optionallysubstituted by cyano, amino, lower alkyl or heteroaryl substituted byone or more lower alkyl(s); R³ and R⁴ are each independently loweralkyl, or R³, R⁴ and nitrogen atom to which they are attached form anoptionally substituted, saturated or partially saturated N-containingheterocyclic group; R⁶ is hydrogen, halogen, lower alkyl, lower alkoxy,halo(lower)alkyl or —NR⁸R⁹ (wherein R⁸ and R⁹ are each independentlylower alkyl, or R⁸, R⁹ and nitrogen atom to which they are attached forman optionally substituted, saturated or partially saturated N-containingheterocyclic group);

is bivalent residue derived from arene or heteroarene; X is direct bondor bivalent residue derived from piperazine, Y is -(A¹)_(n)-(A²)_(m)-wherein A¹ is —O—, —NH—, —N(R⁵)—, —CO—or —NH—CO—, wherein R⁵ is aminoprotective group, A² is lower alkylene, and n and m are independently 0or 1; and Z is N or C(R¹⁰) (wherein R¹⁰ is the same as R⁶ definedabove), or a salt thereof.
 10. The compound of claim 9, wherein R² isphenyl, pyridinyl, pyrimidinyl or thiazolyl, each of which is optionallysubstituted with cyano, amino, lower alkyl or pyrrolyl substituted withone or more lower alkyl; R³ and R⁴ are each independently lower alkyl,or R³, R⁴ and nitrogen atom to which they are attached form a saturatedor partially saturated N-containing heterocyclic group selected from

wherein R¹¹ and R¹² are each independently hydrogen or lower alkyl, andQ is —N(R¹³)—, —O—, —S—, —SO— or —SO₂— wherein R¹³ is hydrogen or loweralkyl; R⁶ is hydrogen, halogen, lower alkyl, lower alkoxy,halo(lower)alkyl or —NR⁸R⁹ (wherein R⁸ and R⁹ are each independentlylower alkyl, or R⁸, R⁹ and nitrogen atom to which they are attached forma saturated or partially saturated N-containing heterocyclic groupselected from

wherein R¹¹, R¹² and Q are as defined above); and

is phenylene, pyridinediyl or indolinediyl, or a salt thereof.
 11. Thecompound of claim 9, wherein R² is phenyl, pyridinyl, pyrimidinyl orthiazolyl, each of which is optionally substituted with cyano, amino,lower alkyl or pyrrolyl substituted with one or more lower alkyl; R³ andR⁴ are each independently lower alkyl; R⁶ is hydrogen, halogen, loweralkyl, lower alkoxy or halo(lower)alkyl; and

is phenylene, or a salt thereof.
 12. The compound of claim 9, wherein R²is phenyl, pyridinyl, pyrimidinyl or thiazolyl, each of which isoptionally substituted with cyano, amino, lower alkyl or pyrrolylsubstituted with one or more lower alkyl; R³ and R⁴ are eachindependently lower alkyl; R⁶ is hydrogen, halogen, lower alkyl, loweralkoxy or halo(lower)alkyl; and

is indolinediyl, or a salt thereof.
 13. The compound of claim 9, whereinR² is phenyl, pyridinyl, pyrimidinyl or thiazolyl, each of which isoptionally substituted with cyano, amino, lower alkyl or pyrrolylsubstituted with one or more lower alkyl; R³, R⁴ and nitrogen atom towhich they are attached form a saturated N-containing heterocyclic groupof the formula

wherein R¹¹ and R¹² are each independently hydrogen or lower alkyl; R⁶is hydrogen, halogen, lower alkyl, lower alkoxy or halo(lower)alkyl; and

is phenylene, or a salt thereof.
 14. The compound of claim 9, wherein R²is phenyl, pyridinyl, pyrimidinyl or thiazolyl, each of which isoptionally substituted with cyano, amino, lower alkyl or pyrrolylsubstituted with one or more lower alkyl; R³, R⁴ and nitrogen atom towhich they are attached form a saturated N-containing heterocyclic groupof the formula

wherein R¹¹ and R¹² are each independently hydrogen or lower alkyl; R⁶is hydrogen, halogen, lower alkyl, lower alkoxy or halo(lower)alkyl; and

is indolinediyl, or a salt thereof.
 15. The compound of claim 1 or apharmaceutically acceptable salt thereof for use as a medicament.
 16. Apharmaceutical composition comprising a compound of claim 1 or apharmaceutically acceptable salt thereof in admixture with apharmaceutically acceptable carrier.
 17. A method for inhibiting ordecreasing Apo B secretion in a mammal, which comprises administering anApo B secretion inhibiting or decreasing amount of a compound of claim 1or a pharmaceutically acceptable salt thereof to the mammal.
 18. Amethod for preventing or treating a disease or condition resulting fromelevated circulating levels of Apo B in a mammal, which comprisesadministering an effective amount of a compound of claim 1 or apharmaceutically acceptable salt thereof to the mammal.
 19. The methodof claim 18, wherein the disease or condition resulting from theelevated circulating levels of Apo B is selected from the groupconsisting of hyperlipemia, hyperlipidemia, hyperlipoproteinemia,hypoalphalipoproteinemia, hypercholesterolemia, hypertriglyceridemia,atherosclerosis, pancreatitis, non-insulin dependent diabetes mellitus(NIDDM), obesity, coronary heart diseases, myocardial infarction,stroke, restenosis and Syndrome X.
 20. The compound of claim 3 or apharmaceutically acceptable salt thereof for use as a medicament.
 21. Apharmaceutical composition comprising a compound of claim 3 or apharmaceutically acceptable salt thereof in admixture with apharmaceutically acceptable carrier.
 22. A method for inhibiting ordecreasing Apo B secretion in a mammal, which comprises administering anApo B secretion inhibiting or decreasing amount of a compound of claim 3or a pharmaceutically acceptable salt thereof to the mammal.
 23. Amethod for preventing or treating a disease or condition resulting fromelevated circulating levels of Apo B in a mammal, which comprisesadministering an effective amount of a compound of claim 3 or apharmaceutically acceptable salt thereof to the mammal.
 24. The methodof claim 23, wherein the disease or condition resulting from theelevated circulating levels of Apo B is selected from the groupconsisting of hyperlipemia, hyperlipidemia, hyperlipoproteinemia,hypoalphalipoproteinemia, hypercholesterolemia, hypertriglyceridemia,atherosclerosis, pancreatitis, non-insulin dependent diabetes mellitus(NIDDM), obesity, coronary heart diseases, myocardial infarction,stroke, restenosis and Syndrome X.
 25. The compound of claim 9 or apharmaceutically acceptable salt thereof for use as a medicament.
 26. Apharmaceutical composition comprising a compound of claim 9 or apharmaceutically acceptable salt thereof in admixture with apharmaceutically acceptable carrier.
 27. A method for inhibiting ordecreasing Apo B secretion in a mammal, which comprises administering anApo B secretion inhibiting or decreasing amount of a compound of claim 9or a pharmaceutically acceptable salt thereof to the mammal.
 28. Amethod for preventing or treating a disease or condition resulting fromelevated circulating levels of Apo B in a mammal, which comprisesadministering an effective amount of a compound of claim 9 or apharmaceutically acceptable salt thereof to the mammal.
 29. The methodof claim 28, wherein the disease or condition resulting from theelevated circulating levels of Apo B is selected from the groupconsisting of hyperlipemia, hyperlipidemia, hyperlipoproteinemia,hypoalphalipoproteinemia, hypercholesterolemia, hypertriglyceridemia,atherosclerosis, pancreatitis, non-insulin dependent diabetes mellitus(NIDDM), obesity, coronary heart diseases, myocardial infarction,stroke, restenosis and Syndrome X.